Mammalian Tribbles Homologs at the Crossroads of Endoplasmic Reticulum Stress and Mammalian Target of Rapamycin Pathways

Cunard, Robyn

doi:https://doi.org/10.1155/2013/750871

Scientifica

On this page

Abstract Introduction Conclusions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2013 | Article ID 750871 | https://doi.org/10.1155/2013/750871

Mammalian Tribbles Homologs at the Crossroads of Endoplasmic Reticulum Stress and Mammalian Target of Rapamycin Pathways

Robyn Cunard^1,2

Academic Editor: G.-P. Zhou, J. L. Barnes, F. Artunc

Received07 Oct 2013

Accepted20 Nov 2013

Published30 Dec 2013

Abstract

In 2000, investigators discovered Tribbles, a Drosophila protein that coordinates morphogenesis by inhibiting mitosis. Further work has delineated Xenopus (Xtrb2), Nematode (Nipi-3), and mammalian homologs of Drosophila tribbles, which include TRB1, TRB2, and TRB3. The sequences of tribbles homologs are highly conserved, and despite their protein kinase structure, to date they have not been shown to have kinase activity. TRB family members play a role in the differentiation of macrophages, lymphocytes, muscle cells, adipocytes, and osteoblasts. TRB isoforms also coordinate a number of critical cellular processes including glucose and lipid metabolism, inflammation, cellular stress, survival, apoptosis, and tumorigenesis. TRB family members modulate multiple complex signaling networks including mitogen activated protein kinase cascades, protein kinase B/AKT signaling, mammalian target of rapamycin, and inflammatory pathways. The following review will discuss metazoan homologs of Drosophila tribbles, their structure, expression patterns, and functions. In particular, we will focus on TRB3 function in the kidney in podocytes. This review will also discuss the key signaling pathways with which tribbles proteins interact and provide a rationale for developing novel therapeutics that exploit these interactions to provide better treatment options for both acute and chronic kidney disease.

1. Introduction

In the age of personalized and targeted medical therapies [1], the treatment of both acute and chronic kidney disease (CKD) remains a formidable challenge. Our treatment options in these diseases are limited and often rely on basic immunosuppression with corticosteroids, steroid-sparing medications, and supportive measures. Both acute kidney injury [2–4] and chronic kidney disease [5–9] are associated with the activation of multiple signaling pathways, which can contribute to persistent organ injury. It is likely that therapeutics that regulate these signaling cascades can be developed to provide more effective and specific approaches for treating diverse kidney diseases. Work over the last decade has elucidated a number of novel signaling molecules that dampen the activation of potentially harmful signaling cascades. One such protein, tribbles may function at the intersection of multiple stress-activated pathways including the mammalian target of rapamycin (mTOR), endoplasmic reticulum (ER) stress, and macro-autophagy pathways. In the following review, we will first discuss metazoan homologs of Drosophila tribbles, their structure, expression patterns, and functions. We will also review the key signaling pathways with which tribbles proteins interact and provide a rationale for developing novel therapeutics that exploit these interactions to provide better treatment options for both acute and chronic kidney disease.

2. TRB Family Members

Tribbles was first described in 2000 as a Drosophila (fruit fly) protein that coordinates morphogenesis by inhibiting mitosis [10–12]. The moniker was based on observations that tribbles mutants (knockdown of tribbles) enter mitosis early, and have over-proliferation of mesodermal cells, and resemble the highly proliferating Tribbles organisms encountered on the science fiction Star Trek television show [10, 13]. Tribbles arrests cells in the G2 phase of the cell cycle, by binding to and inducing proteasome-mediated degradation of String and Twine, cyclin-dependent kinase 25 (CDC25) phosphatases [11]. In the ovary, Tribbles targets migration of the slow border cells (Slbo), (CAAT enhancer binding protein, C/EBP homolog), for rapid degradation via the ubiquitin-proteasome pathway [14, 15]. These early fly studies demonstrated that Tribbles was important in synchronizing sequential cytoskeletal arrangements necessary for coordinating cell division, fate, and morphogenesis [16, 17]. Follow up work in Drosophila has demonstrated that tribbles plays a role in fly memory, central nervous system (CNS) development, and bristle formation (bundles of actin filaments) [18, 19]. Tribbles also reduces Notch signaling during bristle patterning [17].

In Xenopus (African clawed frog), investigators discovered a tribbles homolog Xtrb2, which plays a significant role in development. They discovered two alternatively spliced cDNA sequences, a short and long Xtrb2, which are differentially expressed. Surprisingly, depletion of Xtrb2 delays cell division and induces abnormalities in somite and eye development. These studies suggested that Xtrb2 plays a role in the progression of mitosis and proper formation of the nervous system [20]. Interestingly, GFP-tagged Xtrb2 was transiently associated with mitotic spindles during cell division [20]. In Caenorhabditis elegans (nematode), investigators identified nipi-3, a tribbles-like protein. Nipi-3 is upregulated in response to fungal infection and may play a role in the innate immune response [21]. Follow-up studies have suggested that nipi-3 functions upstream of a glucose regulated protein 78/binding immunoglobulin protein (GRP78/BiP) homolog to induce expression of antimicrobial peptides in a mitogen-activated protein kinase (MAPK)-dependent manner [22, 23]. Thus, these early studies in primitive metazoans demonstrated that tribbles both promotes and blocks cell division, is involved in cytoskeletal dynamics, interacts with the ubiquitin-proteasome degradation system, and regulates innate immunity. The diversity of function is quite remarkable.

In mammalian cells, prior to the discovery of tribbles, investigators identified proteins that were subsequently shown to be homologs of Drosophila tribbles. In 1997, Wilkin and colleagues described c5fw (clone 5 Françoise Wilkin) and c8fw, proteins upregulated in dog thyroid cells chronically treated with thyroid stimulating hormone [24, 25]. In neuronal cells, a homologous protein, novel kinase-like gene induced during cell death (NIPK), increased in neurons deprived of neuronal growth factor and treated with the calcium ionophore, A23187 [26]. The same protein, p65 interacting inhibitor of nuclear factor kappa light chain-enhancer of activated B cells (NF-κB, SINK), was shown to inhibit p65 phosphorylation by Protein Kinase A (PKA, cAMP-dependent kinase) and sensitize cells to tumor necrosis factor (TNF)-induced apoptosis [27]. SKIP3, another homolog, was discovered in human lung, colon, esophageal, and breast tumors [28]. Further work has delineated three mammalian homologs of Drosophila tribbles, which include TRB1 (Trib1, c8fw, SKIP1), TRB2 (Trib2, c5fw, SKIP2), and TRB3 (Trib3, NIPK, SINK, or SKIP3) [24, 26–29]. Notably, human and mouse TRBs share significant amino acid homology and the high evolutionarily conserved sequences support their importance as critical regulators of cellular processes. Among the human TRB proteins, TRB1 and TRB2 share 71% homology, TRB1 and TRB3, 53%, and TRB2 and TRB3 share 54% homology [30].

3. Structure

Early work on TRBs demonstrated that their sequences were similar to classic serine-threonine protein kinases [24, 26, 31]. TRBs have an N-terminal domain, central kinase-like domain, and C-terminal protein-binding domain (Figure 1). However, investigators discovered significant variations in the amino acids in the ATP binding pocket and the kinase catalytic core (review in [18, 30, 32]). Early studies suggested that TRBs could bind to kinase-dependent proteins, but they lacked kinase activity [24, 26]. Thus, TRBs are classified as pseudokinases, and belong to a family of proteins which include Integrin-linked kinase (ILK), Janus tyrosine kinases (JAKs), ErbB3/HER3, and Erythropoietin-producing hepatocyte kinases (EphB6) [33]. The mechanisms of action of TRB homologs remain incompletely understood, though investigators have hypothesized that tribbles homologs function as docking kinases [34], scaffolds that balance complex signaling pathways [35], or allosteric activators of protein kinases [36]. Interestingly, the WNK (with no (K) Lys) proteins lack conserved catalytic lysine residues required for ATP binding [37]. Despite these variations in the catalytic domains, WNK proteins are active kinases and play a significant role in kidney ion transport and blood pressure control [38]. CASK and ErbB3/HER3 were also originally described as pseudokinases, and later discovered to possess kinase activity [39, 40]. It is likely that studies investigating TRBs’ three-dimensional structures will be necessary to determine potential targets and demonstrate kinase activity [41].

There is significant sequence divergence in the N-terminal domains of TRB family members, but the C-terminal domains have two conserved sequences: an E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1) site, which binds an E3 ubiquitin ligase, (also known as RING finger and WD repeat domain protein 2, RFWD2) [42, 43], and a MEK1 (Mitogen activated protein kinase kinase, MAPKK) binding site which mediates interactions with multiple MAPKKs including mixed lineage kinase 3 (MLK3) [44, 45]. TRB3 has a D-box destruction motif, which is important for ubiquitin ligase anaphase-promoting complex/cyclosome and -dependent proteolysis [46]. Additionally, Imajo and Nishida have shown that TRB1 interacts with retinoic acid receptor-α (RARα) and retinoid X receptor-α (RXRα) heterodimers through its pseudokinase domain [47].

4. Expression Patterns

TRB1 is expressed in the liver, kidney, heart, brain, skin, small intestine, bone marrow (BM), peripheral blood leukocytes (PBL), especially monocytes, macrophages and B cells, thyroid gland, white adipose tissue (WAT), and pancreas [48–51]. TRB2 is expressed in the thymus, heart, brain, kidney, lung, skin, spleen, PBL (T and B lymphocytes), and WAT [48, 49]. TRB3 is most highly expressed in the liver and hematopoietic compartments, such as BM, PBL (B cells), spleen, thymus, prostate, heart, kidney, lung, skin, small intestine, WAT, neurons, skeletal muscle, and stomach [26–28, 48, 52–54]. When detailed studies using sensitive means of detection (i.e., real-time PCR) are used, the mRNA of TRB isoforms is ubiquitously expressed. In developmental studies, investigators have observed the expression of TRB2 in a variety of organs during gestation, including the kidneys, mesonephros, testes, heart, eyes, thymus, blood vessels, muscle, bones, tongue, spinal cord, and ganglions [55, 56]. TRB1 was less abundantly expressed in embryonic and adult kidneys than TRB2, and TRB3 was undetectable in embryonic kidneys [55]. Indeed, TRB isoform expression is highly regulated and very context-dependent. TRBs function in both the cytoplasm and nucleus, though investigators have recognized that TRB1 and TRB3 preferentially localize to the nucleus, whereas TRB2 is more often detected in the cytoplasm [32].

TRB3 expression is generally regulated at the transcriptional level [27, 52, 57]. Interestingly, in mouse embryonic stem cells, TRB1 belongs to a subset of mRNA species with extremely short half lives (<1 hr), the authors suggested that the mRNA’s half-life was related to its physiological role, that is, the shorter the half-life, the more critical its role [58]. Studies also suggest that the TRB3 protein is short-lived and protein levels are regulated by proteasome-dependent degradation by the E3 ubiquitin ligase seven in absentia homolog 1 (SIAH1) [59], ubiquitin ligase anaphase-promoting complex/cyclosome Cdh1 [46], and cysteine-dependent aspartate-directed protease 3 (caspase 3) [60].

5. Functions of TRB Isoforms

As previously discussed, tribbles homologs have not yet been shown to have specific kinase function. However, TRB family members play a role in the differentiation of macrophages [51], lymphocytes [52], muscle cells [61], adipocytes [62–64], and osteoblasts [65]. TRBs also coordinate a number of critical cellular processes including glucose and lipid metabolism, inflammation, cellular stress, survival, apoptosis, and tumorigenesis. Moreover, they regulate and interact with a number of transcription factors. Table 1 describes these transcription factors which include: activating transcription factor 4 (ATF4) [66–68], ATF5, C/EBPβ [63, 69], C/EBPα [70, 71], C/EBP homologous protein (CHOP) [57], NF-κB [27, 50] Forkhead box protein/forkhead in rhabdomyosarcoma O1 (FOXO1) [72], FOXO3a [73], FOXP3 [74], PPARγ [75], RARα, and RXRα [47]. However, the function of TRB isoforms in the kidney is not completely understood.

5.1. TRB1

The only investigation of TRB1 and its association with renal disease demonstrated that it is a peripheral blood biomarker of chronic immune-mediated rejection in kidney transplant patients [49]. The investigators also observed higher TRB1 expression in renal biopsies with rejection and in a rodent model of chronic cardiac vasculopathy, suggesting that it could be a useful biomarker for other solid-organ transplants. Notably, in their study, TRB1 was primarily expressed by antigen-presenting cells and activated endothelial cells [49]. The transcription factor FOXP3 is a specific marker of regulatory T cells (Tregs) and its deficiency is associated with autoimmune diseases and inflammation [76]. FOXP3⁺ Tregs may facilitate graft tolerance and promote long-term organ transplant survival [77]. Recent work suggests that TRB1 binds to Foxp3 in Tregs [74]; however, the significance of this interaction has not yet been fully explored. TRB1 expression increases in chronically inflamed human atherosclerotic arteries and reduces vascular smooth muscle cell proliferation and chemotaxis [35, 78]. TRB1 also regulates lipoprotein metabolism [79]. Hepatic-specific overexpression of TRB1 reduces plasma triglycerides (TG) and cholesterol by reducing very low-density lipoprotein (VLDL) production, and TRB1 knockout mice have elevated TG and cholesterol [79]. Not surprisingly, variations in TRB1 loci in humans are associated with increased plasma lipoproteins and risk of coronary artery disease [51, 80, 81]. In white adipose tissue (WAT) TRB1 expression is upregulated during acute (lipopolysaccharide, LPS) and chronic inflammation (db/db mice), and TRB1 heterozygous knockout mice have impaired cytokine gene expression in white adipose tissue (WAT) and are protected from weight gain and adiposity when fed a high fat diet. The investigators further demonstrated that TRB1 interacts with the NF-κB subunit RelA (p65) and affects RelA transcriptional activity via direct physical interaction upon promoter recruitment. Thus, in adipocytes, TRB1 is a nuclear transcriptional coactivator for NF-κB, and induces the expression of pro-inflammatory cytokines [50]. These studies suggest that in the liver, TRB1 positively impacts lipoprotein metabolism, but in WAT TRB1 increases inflammatory cytokine expression, which could ultimately contribute to organ dysfunction.

A number of studies have confirmed that macrophages can be differentially activated into different functional subtypes. M1 cells are classically activated macrophages with pro-inflammatory functions. In contrast, M2 macrophages are alternatively activated, exert anti-inflammatory effects, and are involved in wound healing, tissue repair, and cancer cell growth [82–84]. Early work suggested that in macrophages, TRB1 negatively regulates C/EBPβ (nuclear factor of IL-6, NF-IL6) expression and LPS-stimulated TRB1-deficient macrophages have higher expression of prostaglandin E synthase and Lipocalin 2/Neutrophil gelatinase-associated lipocalin (Lcn2/Ngal) and lower IL-12 expression [85]. TRB1 may also play a role in macrophage migration [86]. Recent follow up studies demonstrate that TRB1 plays a critical role in differentiation of tissue-resident M2-like macrophages and eosinophils by regulating C/EBPα expression [51]. Dr. Akira’s laboratory demonstrated that TRB1 knockout mice have less adipose tissue and this is associated with augmented lipolysis. Interestingly, this defect was rescued by supplementation of M2 macrophages, demonstrating that TRB1 and M2 macrophages play a critical role in adipose tissue maintenance and suppression of metabolic disorders. TRB1 may also inhibit host responses to entamoeba infections [87]. These studies all support the concept that TRB1 plays a central role in the cross-talk between adipose tissue, the immune system, and metabolic homeostasis [88, 89].

5.2. TRB2

In the fetal kidney, TRB2 is expressed in the comma, S-shaped bodies [90], podocytes, and the mesangium of the developing glomeruli, as well as in the ureteric bud tips. However, TRB2 mutant mice are functionally and structurally normal. The authors suggested that TRB2 may play a minimal role during kidney and mouse development [55]; however, the possibility of redundant TRB function was not completely explored, nor were the mice stressed. In murine hematopoietic stem cells, retroviral expression of TRB2 induces acute myelogenous leukemia and degradation of C/EBPα [70, 71]. TRB2 maintains the oncogenic properties of melanoma cells, and TRB2 knockdown reduces cell proliferation, colony formation, and wound healing [73]. In contrast, in certain cytokine-dependent hematopoietic cell lines, TRB2 modulates apoptosis, but this effect is absent in adherent cells, which is possibly related to survival signals associated with adhesion [91]. TRB2 suppresses adipocyte differentiation by inhibiting AKT and C/EBPβ [69]. Downregulation of TRB2 potentiates LPS-induced IL-8 production via MAPK pathways [92], and TRB2 expression is highly upregulated in human atherosclerotic plaques. In primary human monocyte-derived macrophages, TRB2 reduces IL-10 mRNA expression, suggesting that TRB2 may play a role in plaque instability [93]. Thus, the functions of TRB2 are quite diverse, but clearly TRB2 plays a role in inflammation and cellular differentiation including tumorigenesis.

5.3. TRB3

To date, TRB3 has been the most intensely studied mammalian TRB isoform. TRB3 is expressed in the kidney [28, 48], and our group has observed TRB3 expression in podocytes and tubular cells [53]. In the kidney, our studies suggest that TRB3 inhibits inflammatory cytokines and chemokines, as TRB3 inhibits podocyte expression of monocyte chemokine protein 1 (MCP-1) [53]. Kuo and colleagues have similar findings, and knockdown of TRB3 in sensitized mast cells increases expression of IL-6, MCP-1, TNFα, and IL-4, suggesting again that TRB3 may negatively regulate the expression of pro-inflammatory cytokines and chemokines [94]. Early work by Marc Montminy’s group demonstrated that TRB3 binds to and masks phosphorylation of Protein Kinase B/AKT at Threonine (Thr)³⁰⁸ and Serine (Ser)⁴⁷³ residues, thereby reducing insulin-stimulated glucose output in liver cells [95]. Later in this review, we will discuss the impact of AKT phosphorylation on kidney pathophysiology. In vivo, TRB3 expression increases in the livers of fasted mice and functions to increase glucose output [95, 96], though there has been controversy regarding the ability of TRB3 to block phosphorylation of AKT [75, 97]. TRB3 also inhibits insulin-induced activation of S6 kinase 1 by mammalian target of rapamycin [98], and stimulates liver lipolysis by promoting the degradation of acetyl-Coenzyme A carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis [42]. TRB3 is upregulated in the skeletal muscle of patients with Type II diabetes and TRB3 over-expression in muscle cells blocks insulin-stimulated glucose transport and impairs phosphorylation of AKT, extracellular-signal regulated kinase (ERK), and insulin receptor substrate-1 (IRS1) [54]. TRB3 impacts glucose uptake and oxidation oppositely in muscle and fat, and Liu and colleagues have postulated that TRB3 may function as a sensor of nutrient availability [99]. Interestingly, recent work suggests that TRB3 inhibition may improve insulin sensitivity in vivo primarily in a PPARγ-dependent manner, independent of changes in AKT activity [75]. These studies demonstrate that TRB3 regulates insulin sensitivity and lipolysis, and may be an excellent therapeutic target for insulin resistance [42, 95, 98, 100–102].

6. TRB Knockout Mice

All three TRB isoforms have been successfully knocked-out in mice and investigators have postulated that the viability of each knockout, could be related to compensation by other TRB family members. Though to date, upregulation of other TRB isoforms in the single TRB2 and TRB3 knockout mice has not been observed [48, 55]. The development of double and triple knockout mice should reveal whether TRB isoforms have redundant function [30, 55]. In 2007, Okamoto et al. [48] developed a strain of TRB3 knockout mice, and they did not observe alterations in fasting and postprandial glucoses, lipids, insulin, leptin, hepatic insulin sensitivity or lipid metabolism. They proposed that constitutive loss of TRB3 was not sufficient to alter the maintenance of glucose and energy homeostasis, and future challenge studies were necessary to evaluate TRB3 function [48]. Dr. Shizuo Akira’s group has developed constitutive knockout of TRB1, TRB2, and TRB3 mice [51] and each of these mice strains are viable. Though there are reports of higher perinatal mortality in TRB1 homozygous knockout mice on the C57BL/6 background [50], and the female TRB1 knockout mice are infertile [85]. As discussed, many studies have suggested that TRB3 can induce insulin-resistance; thus, it will be of interest in the future to evaluate whether constitutive TRB3 knockout alters insulin signaling and fasting glucoses in murine models of Type 1 and 2 diabetes. Örd and colleagues independently developed another strain of TRB3 knockout mice and discovered that TRB3 regulates mast cell survival and function [103]. TRB2 knockout mice also develop normally [55]; however, investigations of these mice in acute and chronic disease models have not yet been published.

Recently, two groups have shown that partial TRB3 gene silencing (by RNAi technology) alleviates diabetic cardiomyopathy and diabetic atherosclerosis. In a model of diabetic atherosclerosis, male apoE/low density lipoprotein (LDL) receptor double knockout mice were fed a high fat diet and then treated with low dose STZ. TRB3 knockdown reduced the extent of atherosclerosis, increased plaque stability, and reduced macrophage apoptosis and migration [104]. In a model of diabetic cardiomyopathy, rats were treated with a high fat diet and STZ. The rats with TRB3 knockdown had improved insulin resistance and cardiac function [105]. In both studies, the efficiency of TRB3 knockout in the aorta and heart was about 70%, and serum glucoses were dramatically improved. Thus, in these studies, improvements in diabetic cardiomyopathy and atherosclerosis could have been related to improved metabolic control. In murine heart tissue, TRB3 expression also increases in experimental myocardial infarction. Interestingly, transgenic mice with cardiac-specific overexpression of TRB3 had reduced cardiac glucose oxidation rates and were sensitized to infarct expansion and cardiac myocyte apoptosis in the infarct border zone after myocardial infarction [106]. TRB3 appears to have both beneficial and deleterious effects in multiple tissues. Our studies in lymphocytes and the kidney suggest that TRB3 inhibits inflammation, and we postulate that augmented expression of TRB3 may improve outcomes in acute and chronic kidney diseases. Further studies with TRB3-specific over-expression in the kidney, especially in podocytes and tubular cells will be of great interest to identify whether manipulation of TRB3 expression is therapeutically efficacious in both acute and chronic kidney diseases.

7. TRB3 and Cellular Survival and Apoptosis

Early studies suggested that TRB3 induces apoptosis. In brain tumor cells, TRB3 is upregulated by cannabinoids and activates autophagy and caspase-mediated apoptotic pathways [107]. Interestingly, this effect was limited to transformed cells and not observed in nontransformed neuronal cells [107]. TRB3 also mediates human monocyte-derived macrophage apoptosis [108], and knockdown of TRB3 reduces endoplasmic reticulum (ER) stress-induced apoptosis [57]. TRB3 promotes apoptosis in pancreatic β-cells [45] and chondrocytes [109]. However, in podocytes [53] of the kidney, we have not observed apoptosis when TRB3 is over-expressed. In fact, TRB3 does not universally cause cell death. TRB3 is induced five-fold by erythropoietin and is associated with erythroblast survival [62]. In postmitotic neuronally differentiated PC12 cells, coexpression of TRB3 with ATF4 prevents ATF4-induced apoptosis [110] and TRB3 can function as a pro-survival factor in glucose-starved PC-3 prostate cancer cells [111] and bone marrow-derived mast cells [103]. Thus, TRB3’s effects on survival or apoptosis are likely cell type and context dependent. Indeed, Shimizu and colleagues postulate that TRB3 serves as a switch between cellular survival and apoptosis. Caspases play a central role in the execution-phase of apoptosis, and they demonstrated that TRB3 prevents the activation of caspase 3 by nuclear translocation of procaspase 3. However, in conditions of prolonged stress, TRB3 is cleaved by caspase 3 and no longer inhibits caspase 3-induced apoptosis [60]. Again, TRB3 function is very context and cell type-dependent, suggesting that TRB family members may sense, integrate, and respond to diverse signals to promote homeostatic function.

8. Cell Cycle

During the development and differentiation of multicellular organisms, precise control over the timing of cell cycle progression is critical, as premature cellular divisions can disrupt morphogenesis [112]. Therefore, cells have developed a number of mechanisms to prevent premature entry into the synthesis (S) and mitosis (M) phases of the cell cycle [113]. The initiation of mitosis is controlled by a catalytic subunit cyclin-dependent kinase 2 (CDC2), and a regulatory subunit, Cyclin B. CDC25C dephosphorylates Cyclin B-CDC2 and triggers entry into mitosis. Early work suggested that Drosophila tribbles slows cell cycle progression by inducing the degradation of a CDC25C homolog [10, 11] and Tribbles overexpression in the Drosophila wing greatly reduces the number of cells per wing [11]. In mammalian cells, TRB3 deletion upregulates the expression levels of CDC20 and CDC25A [46], and TRB3 regulates the stability of CDC25A, a cell-cycle regulator that is degraded in response to DNA damage [114, 115]. However, it is not clear whether TRB3-induced degradation of CDC25A affects cell cycle progression. In lymphocytes, we have shown that TRB3 blocks cells in the G2 phase of the cell cycle [52], and transcriptional studies suggest that TRB3 inhibits activation of the Cyclin B1 promoter [116]. In a similar manner, in endothelial cells TRB3 mediates homocysteine-induced inhibition of cell cycle progression by up-regulating expression of p27(kip1) [117]. Cell cycle progression requires multiple levels of regulation and it is likely that TRB3 modulates the expression of other key cell cycle modulators including p21 and p53.

9. Inflammation

Early investigations by Kiss-Toth’s group demonstrated that TRBs interact with MAPK kinases to regulate MAPK [35]. They demonstrated that all TRB isoforms regulate inflammatory signaling networks, by binding to c-Jun N-terminal kinases (JNKs), and p38 to regulate IL-8 production [118]. As previously discussed, TRB1 is a novel binding partner of FOXP3, a master regulator of regulatory T cells [74]; thus, it is likely that TRB1 plays a significant role in immune cell function. Furthermore, TRB1 deficiency impairs cytokine gene expression in white adipocytes [50], and TRB1 is involved in cytokine and chemokine expression of mast cells [94] and polarization of M2 macrophages [51]. Helicobacter pylori is a bacterial pathogen that causes stomach inflammation and in gastric epithelial cells TRB3 enhances Toll-like receptor 2 (TLR2)-mediated NF-κB activation and chemokine induction in response to H. pylori LPS [119]. Our studies have also demonstrated that TRB3 mediates anti-inflammatory effects in lymphocytes, podocytes, and renal tubular cells [52, 53, 116]. These studies all support the concept that TRBs play a significant role in immunity. Similar to their effects on insulin sensitivity and metabolism, their seemingly contradictory effects in diverse cell types likely function to control the extent of the inflammatory response and may provide a means of balancing cross-talk between solid organs and the immune system.

10. Regulation of Expression of TRB3

Multiple cellular stressors including nutrient and essential amino acid deprivation, activation of phosphatidylinositol-3-kinase (PI3K), ER stress, thapsigargin, free fatty acids, fasting, cadmium, TNF, phorbol esters, arsenite, nerve growth factor depletion, hypoxia, insulin, oxidized LDL, ethanol, and IL-3 augment TRB3 expression [26–28, 53, 57, 66, 67, 72, 95, 103, 108, 111, 120–123]. In contrast, phosphodiesterase inhibition, dexamethasone, cyclic adenosine monophosphate (cAMP), IL-3 deprivation, and activation of FOXO-1 reduce TRB3 expression [63, 72, 103]. Interestingly, in prostate cancer cells with constitutively active PI3K signaling, TRB3 expression is down-regulated in response to rapamycin (an mTOR complex 1, mTORC1 inhibitor) [111]. In neuronal cells, chronic lithium treatment downregulates TRB3 expression suggesting that TRB3 could play a role in bipolar affective disorder [124]. Although, TRB3 has not yet been shown to directly regulate p53 activity, in human colon cancer cells, genotoxic stress (chemotherapeutic agents) down-regulates TRB3 in a p53-dependent and p53-independent manner [125]. Acetylation of TRB3 may also regulate its activity. Yao and colleagues demonstrated that TRB3 was upregulated and hypoacetylated in a rat model of prenatal alcohol exposure [126]. Thus, the regulation of TRB3 and its other family members is extremely complex, again related to its function as a regulator and integrator of many cellular signaling pathways.

Investigators have characterized 3 tandem 33 base pair (bp) repeats in the human TRB3 promoter [57, 67]. Each of these repeats have a C/EBP-ATF composite site that resembles sequences in the Nutrient Sensing Response Element (NSRE-1) in the asparagine synthetase promoter and the Amino Acid Response Element (AARE) in the CHOP promoter [57, 67]. Cellular stress upregulates CHOP and ATF4, which in turn activate the 33 bp repeats in the human TRB3 promoter [57, 67]. In our studies in lymphocytes and podocytes, both C/EBPβ and CHOP bind to the proximal TRB3 promoter and drive TRB3 transcription [52, 53]. Other investigations suggest that PPARα [96] and FOXO1 also regulate TRB3 promoter activity [72].

11. Mechanism of Action

Before we discuss the effects of TRB3 on AKT phosphorylation and function, it is important to provide a framework for understanding AKT, as it plays a central role in transducing signals that affect cell survival, proliferation, inflammation, and metabolism. Moreover, AKT regulates hundreds of downstream targets (review in [127]), many with opposing functions. AKT is a serine-threonine kinase and full activation of AKT by growth factors, including insulin requires phosphorylation of Ser⁴⁷³ residues by the mTOR complex 2 (mTORC2) and phosphorylation of Thr³⁰⁸ residues by 3-phosphoinositide-dependent protein kinase-1 (PDK1) [128]. Phosphorylation of AKT at Thr⁴⁵⁰ residues may also impact kinase activity and stability [129].

AKT is activated in the cortices of diabetic mice by multiple stimulators including Ang II and reactive oxygen species (ROS) [130–134], and stimulates the formation of extracellular matrix, including fibronectin [135]. Early work suggested that lower AKT phosphorylation reduces cellular survival [136, 137]; however, more recent work suggests that differential phosphorylation of AKT at Thr³⁰⁸ and Ser⁴⁷³ residues likely exerts diverse effects. Indeed, rat glomeruli injured with protamine sulfate have higher albumin permeability associated with increased phosphorylation of and blockade of mTORC2 reduces phosphorylation of and albumin release [138]. In parallel, high glucose conditions and advanced glycation endproducts increase phosphorylation of in rat podocytes and this is associated with cleaved caspase 3 and apoptosis [139]. Inflammatory mediators such as TNFα and IL-6 increase phosphorylation of AKT and reduce nephrin promoter activity in reporter murine podocytes [140]. Thus, the relevance of differential phosphorylation of AKT on Thr³⁰⁸, Ser⁴⁷³, and Thr⁴⁵⁰ residues is complex and not completely understood. Recent studies suggest that downstream substrates may require different levels of AKT activity, and differential AKT phosphorylation patterns may provide a mechanism for integrating diverse cellular stimuli. Moreover, differential phosphorylation of AKT at Thr³⁰⁸ and Ser⁴⁷³ residues may confer substrate specificity and facilitate splitting of upstream signals into discrete outputs [141, 142].

At this time, despite the lack of evidence of kinase activity, investigators have elucidated a number of functions of TRB family members, most of which involve direct protein/protein interactions and degradation of target molecules. As previously discussed, TRB3 binds to and masks phosphorylation of AKT at Thr³⁰⁸ and Ser⁴⁷³ residues. This work has been confirmed by a number of groups [61, 95, 102, 123, 143, 144] and disputed by others [75, 97]. Indeed in lymphocytes, we have not observed inhibition of phosphorylation of AKT at Thr³⁰⁸ residues associated with over-expression of TRB3 [116]. Our recent work in podocytes, tubular cells, and a murine model of Type 1 diabetes suggests that TRB3 selectively inhibits phosphorylation of AKT at Ser⁴⁷³ residues [145], and other groups have similar observations [146]. These findings suggest that TRB3 may fine-tune AKT activation [143] to modulate multiple physiological inputs. To add a layer of complexity, FOXO1 an AKT-target protein, also plays an important role in hepatic glucose output [147]. Unphosphorylated FOXO1 localizes in the nucleus and drives the transcription of genes important in gluconeogenesis and glycogenolysis. Through AKT, insulin induces the phosphorylation of FOXO1, promoting its exclusion from the nucleus, ubiquitination, and degradation [148–150]. Accili’s group demonstrated that FoxO1 activates AKT and inhibits TRB3 expression in hepatocytes [72]. Thus, there is significant cross-regulation among insulin, AKT, FOXO1, and TRB3. We hypothesize that the complex regulation of TRB3 and its interaction with multiple metabolic signaling cascades may provide a mechanism of harmonizing nutrient availability with complex physiologic programs such as growth, proliferation, and differentiation [143].

TRBs do not have a DNA-binding domain, but they interact with transcription factors, especially members of the basic region leucine zipper (bZIP) family and can inhibit their action by direct binding or by inducing proteolysis. TRB1 and TRB2 induce degradation of C/EBPα, but TRB3 doesn’t [43, 70, 71, 151]. TRB2 and TRB3 bind to C/EBPβ [63, 69] and TRB3 binds CHOP [57] and ATF4 and regulates ATF4’s activity [28, 66, 67]. TRB family members also bind factors that regulate NF-κB and AP-1 [27, 35, 152], and TRB isoforms bind nuclear receptors including PPARγ, RARα, and RXRα [47, 64].

Besides binding to and/or mediating the proteolysis of key transcription factors TRB3 also degrades ACC1 [42], Smad ubiquitin regulatory factors (SMURFs) [65, 153], and caspase-3 [60]. TRB1 and 3 bind to MAPKK and regulate their activity [35]. In vascular smooth muscle cells, TRB1 binds to MKK4 and inhibits JNK activity [35, 78]. TRB3 also interacts with the mixed lineage kinase 3 (MLK3) and compromises mitochondrial integrity and suppresses cellular survival [45]. TRB3 binds to the Bone Morphogenic Proteins (BMP) Type II (BMPRII) receptor and promotes BMP4 signaling [65]. The general theme of these studies is that TRB family members alter transcriptional and posttranscriptional events by interacting with transcriptional and signaling regulators and either block their phosphorylation or target the proteins for degradation.

12. TRB3 and Cancer

Early work demonstrated that TRB3 (SKIP3) was expressed in human lung, colon, esophageal, and breast tumors [28, 154]. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that plays a role in kidney development and disease [155]. Recent investigations have demonstrated that TRB3 is a master regulator of Notch through the MAPK-ERK and Transforming Growth Factor β (TGFβ) pathways, and is required for the growth of basal-like breast cancer [156, 157]. Indeed, TRB3 may serve as a prognostic marker in breast cancer [158–161]. In HepG2 cells, TRB3 plays a role in tumor progression and metastases, by augmenting TGFβ-SMAD3-transcriptional activity and inducing epithelial-mesenchymal transition (EMT) [65, 153]. TRB3 expression is upregulated in nonsmall cell lung cancer (NSCLC) and expression correlates with poor survival in patients [157]. In hepatocellular carcinoma cells and gliomas, cannabinoids increase TRB3 expression [107, 162]. In human hepatoma cells, a novel NF-κB inhibitor, dehydroxymethyl-epoxyquinomicin (DHMEQ) promotes TRB3 mRNA induction and inhibits cell growth and apoptosis [163]. Investigators have postulated that TRB3 may facilitate the growth of cells in nutrient-limiting conditions [28, 111]. TRB3 may also play a role in cell cycle control, cell survival, DNA repair, and genome stability by interacting with Ct interacting protein (CtIP) [154] and polydeoxynucleotide cytidine deaminases APOBEC3A and APOBEC3C. These interactions inhibit nuclear DNA editing, suggesting that TRB3 may be an important guardian of genome integrity [164].

TRB1 is overexpressed in acute myelogenous leukemia (AML) [165], can induce AML in mice [71, 166], and a TRB1 somatic mutation was observed in a human case of Down syndrome-related acute megakaryocytic leukemia [167]. In contrast, TRB2 expression is upregulated in only a subset of patients with AML [70, 168] and those with T acute lymphoblastic leukemia [169]. TRB2 may also be involved in the disease progression of high-risk chronic lymphocytic leukemia (CLL) patients [170]. The oncogenic potential of TRB isoforms in acute leukemias has been recently reviewed and we direct readers to this thoughtful review [171].

TRB1 is over expressed in follicular thyroid carcinoma [172], ovarian cancers [173], and in JAK2V617F mutation-negative patients with essential thrombocytosis [174]. TRB2 expression has also been associated with lung cancers [151], and in melanomas, TRB2 facilitates growth and survival by down-regulating FOXO3a activity [73]. Recent work suggests that TRB2’s oncogenic potential is related to its ability to integrate complex signaling pathways including Wnt/β-catenin, Hippo/Yes-associated protein (YAP), and C/EBPα pathways in liver cancer cells [175]. Thus, tribbles family members play a significant role in cancer development and progression (review in [30]).

13. Clinical Correlations

In humans, a gain-of-function TRB3 Glu84Arg (arginine replaces glutamine at position 84) polymorphism is associated with insulin resistance, carotid atherosclerosis, and cardiovascular risk [176–178]. This polymorphism in exon 2 of TRB3 is associated with reduced nitric oxide production in human endothelial cells [179], and plasma levels of C-peptide in humans. TRB3 reduces insulin secretion from pancreatic beta cells and mice over-expressing TRB3 Glu84Arg in beta cells have lower beta cell mass, associated with less proliferation and enhanced apoptosis [68]. The impact of this polymorphism in humans has been recently reviewed [180]. Oberkofler and colleagues evaluated TRB3 levels in the visceral abdominal fat and the liver in obese humans and observed aberrant hepatic TRB3 transcript levels. Additionally, there was a correlation between mRNA levels of TRB3 and plasma insulin [181]. TRB3 is also upregulated in the skeletal muscle of patients with Type II diabetes [54]. Fibrates are ligands of PPARα and commonly used to treat hypertriglyceridemia, and we have previously shown in lymphocytes that fibrates potently augment TRB3 expression, independent of PPARα expression [52]. In both animal and human studies, PPARα ligands are therapeutically efficacious in diabetic nephropathy [182–184]. Fibrates reduce C-reactive protein (CRP) and IL-6 in patients with Rheumatoid Arthritis [185], and we speculate that the beneficial effects of PPARα ligands may be related to augmented lymphocyte TRB3 expression [52, 96].

We have already discussed that variations in TRB1 loci in humans are associated with increased plasma lipoproteins and risk of coronary artery disease [51, 80, 81]. There are also associations of TRB1 gene variants with liver enzyme expression [81], and emerging evidence suggest an association between sleep duration and lipid metabolism. Interestingly, investigators observed that TRB1 gene variants were independently associated with sleep length and lipid metabolism, and there was a significant increase in TRB1 mRNA expression in the peripheral blood mononuclear cells of people restricted to 4 hrs of sleep compared to those with normal sleep duration [186]. Epidemiological studies demonstrate a strong relationship among shortened sleep duration, obesity, and abnormal glucose metabolism [187]. Further work should elucidate whether alterations in TRB isoform expression provide a mechanistic link between sleep duration and metabolic homeostasis.

Autoimmune uveitis is an inflammatory disorder of the eye, and in 2005, Zhang and colleagues discovered in humans that TRB2 is a uveitis-associated autoantigen [188]. Although follow-up studies in uveitis have not been published, TRB2 auto-antibodies have been detected in patients with narcolepsy, a disorder characterized by abnormal daytime sleepiness [189]. Hypocretin (orexin) neurons regulate sleep and wakefulness, and disturbances of the hypocretin system have been directly linked to narcolepsy. Investigators discovered TRB2 auto-antibodies target and lead to the disappearance of hypocretin neurons [190, 191]. Indeed anti-TRB2 antibodies were injected intra-cerebro-ventricularly into mice and they induced narcolepsy-like attacks [192]. Additionally, TRB2 is expressed in tissues of patients with inflammatory bowel disease and may regulate Toll-like receptor 5 signaling [193]. Thus, all TRB family members have been associated with and may modulate diverse human diseases.

The TRB family interacts with and regulates multiple cellular signaling cascades, including the MAPK, insulin signaling-AKT, Notch, cell cycle, and transformation pathways. Our studies suggest that TRB3 may function at the nexus of the ER stress, mTOR, and autophagy pathways. We will first briefly summarize the functions of these pathways and then their interactions with TRB3.

14. Endoplasmic Reticulum Stress

The endoplasmic reticulum (ER) folds, modifies, and degrades secretory and transmembrane proteins. Pathophysiological stress conditions, including nutrient deprivation, nutrient excess, altered protein glycosylation, and oxidative stress interfere with normal protein folding. Accumulation of misfolded and unfolded proteins induces their aggregation and subsequent cellular toxicity. Thus, to alleviate the accumulation of ER proteins, a complex intracellular signaling pathway known as the Unfolded Protein Response (UPR) is activated [194–196]. The UPR represses protein synthesis and increases ER chaperone content to restore normal ER function, however when these pathways are overwhelmed by sustained ER stress, the UPR initiates pro-apoptotic pathways [197–199] and autophagy [7].

In mammalian cells, there are three major arms of the UPR: (1) inositol requiring protein-1α/X box binding protein-1 (IRE1α/XBP-1), (2) protein kinase RNA (PKR)-like ER kinase (PERK), and the (3) activating transcription factor-6 (ATF6) pathways. The PERK pathway rapidly attenuates protein translation, whereas the ATF6 and the IRE1α/XBP-1 cascades transcriptionally upregulate ER chaperone genes that promote proper folding and degradation of proteins, allowing the folding machinery of the ER to catch up with the backlog of unfolded proteins. A number of groups, including ours have documented activation of the ER stress response in the diabetic kidney [53, 200] and ER stress is activated in acute kidney injury and other chronic kidney diseases [201–205]. Moreover, over-expression of ER stress-associated molecules, including chemical chaperones that improve ER folding can reduce ER stress and improve outcomes in kidney disease [205–208].

15. Mammalian Target of Rapamycin (mTOR)

Another key signaling system in the kidney is mTOR, which is a conserved serine/threonine kinase modulated by growth factors and cellular energy status [9, 209–212]. Mammalian TOR forms two distinct molecular complexes known as mTOR complex 1 (mTORC1) and mTORC2. MTORC1 regulates growth, autophagy, survival and metabolism, whereas the role of mTORC2 in cellular biology is incompletely understood. In podocytes, knockout of mTOR disrupts both mTORC1 and mTORC2 function and alters autophagy flux [213]. Both knockdown and overexpression of mTORC1 in podocytes cause proteinuria in animal models, and human diabetic kidney disease has been associated with enhanced mTORC1 function [214]. Besides regulating the phosphorylation of AKT at Ser⁴⁷³ and Thr⁴⁵⁰, mTORC2 also phosphorylates serum/glucocorticoid-regulated kinase-1 (SGK-1) and protein kinase C (PKC) to regulate actin cytoskeletal dynamics, body growth, motility, and survival [215, 216]. Through SGK-1, mTORC2 increases fibronectin expression in high glucose conditions and mTORC2 may regulate nephromegaly, matrix expansion, and excessive sodium reabsorption (potentially involving the epithelial sodium channel ENaC) in diabetic nephropathy [217, 218]. In stress-associated conditions, podocyte-specific knockout of rapamycin-insensitive companion of mTOR (Rictor, a component of mTORC2) causes proteinuria [214]. In podocytes, rapamycin reduces Rictor expression and phosphorylation of AKT at Ser⁴⁷³ and this is associated with a reduction in expression of nephrin [219]. Recent work suggests that inhibition of mTORC2 function inhibits inflammation in rodent inflammatory models [220] and reduces IL-6 expression in stem cells [221]. Indeed, many studies have emphasized the importance of tight regulation mTORC pathways in renal pathophysiology.

16. Autophagy

Macroautophagy (referred to as autophagy) preserves homeostasis by degrading long-lived proteins and dysfunctional organelles [222, 223]. Autophagy has both cytoprotective or cytocidal effects, and dysregulation of autophagy contributes to podocyte dysfunction in diabetic nephropathy [224]. MTORC1 (which is activated by AKT) inhibits autophagy, and dysregulation of mTORC1 activity disrupts autophagy flux [213]. Autophagy begins with the formation of double-membraned, autophagosomes, which sequester intracellular components. This process is activated by class 3 phosphoinositide-3-kinase and beclin (autophagy-related gene/Atg 6). Cytosolic LC3-I (microtubule-associated protein light chain 3) is conjugated to phosphatidylethanolamine to form LC3-II and recruited to the autophagosomal membrane. Next, autophagosomes fuse with lysosomes to form autophagolysosomes and the intracellular contents, including membrane-bound LC3-II are degraded. Interestingly, fibrates which augment TRB3 expression [52], modify expression of LC3-II [225].

17. TRB3 at the Crossroads of ER Stress, mTORC Function, and Autophagy

Recent reviews have focused on interactions between ER stress, autophagy, and mTORC, as dysregulation of these pathways can contribute to acute and chronic kidney disease [7, 226]. We have discussed that in renal tubular cells and podocytes that TRB3 preferentially blocks the phosphorylation of AKT at Ser⁴⁷³, suggesting that TRB3 may inhibit mTORC2 function. Indeed, our recent unpublished studies suggest that TRB3 may bind to Rictor, to modulate mTORC2 activity. Thus, TRB3 likely functions at the intersection of these complex signaling networks (Figure 2). Autophagy can originate from the ER membrane and be triggered by ER stress [227, 228]. Studies suggest that the IRE1α/XBP arm of ER stress activates autophagy, by phosphorylating B-cell lymphoma 2 (Bcl-2) and preventing its interaction with Beclin-1 [229–231]. PERK, another ER stress-associated sensor, mediates conversion of LC3-I (free form) to LC3-II (membrane-bound form), a key step in the induction of autophagy [232]. Additionally, in glioma cells, ER stress induces TRB3, which modifies induction of autophagy [107]. Investigators have speculated that autophagy may supplement ER-associated degradation to reduce the accumulation of misfolded proteins and improve cellular viability [7]. Thus, TRB3 an ER stress-associated protein, by its effects on AKT can modulate mTORC, which in turn activates autophagy. All of these signaling cascades are dysregulated in the injured kidney, and TRB3 is situated at the nexus of these complex pathways. We postulate that manipulation of TRB3 expression is likely to exert significant effects in both acute and chronic kidney disease.

Figure 2

TRB3 at the crossroads of ER stress and mTORC function. Acute and chronic kidney disease are associated with activation of the Endoplasmic Reticulum Stress pathway. During ER stress Protein kinase RNA (PKR)-like ER kinase (PERK) phosphorylates eukaryotic translation initiation factor α (eIF2α) and inhibits protein translation. Additionally, there is selective translation of activating transcription factor-4 (ATF4), which induces expression of C/EBP homologous protein (CHOP) and drives TRB3 expression. Kidney disease is also associated with activation of mTORC and inhibition of autophagy flux. We propose that in the kidney, TRB3 binds to Rictor and mTORC2 and inhibits phosphorylation of . This in turn reduces inflammatory gene expression (IL-6 and MCP-1) and potentially modifies activation of mTORC1 and autophagy.

18. Conclusions

It is clear that TRB family members exert diverse and somewhat contradictory roles in development, cellular differentiation, survival, metabolic homeostasis, inflammation, and tumorigenesis [233]. TRB isoform knockout mice are viable without obvious developmental or pathophysiological abnormalities; however, when the mice are stressed, the relevance of TRB function becomes more obvious. The diversity of function is quite remarkable and suggests that TRB isoforms may not function in a simple manner by either turning on or off signaling cascades. It is tempting to speculate that TRB family members dampen or augment physiologic signaling cascades that impact cross-talk among diverse tissues including the immune system [234]. This review has emphasized that tribbles homologs interact with pathways that have hundreds of downstream targets; thus, it is likely that they serve as sensors and integrate and fine-tune molecular responses to diverse stimuli. This sensing and integration function may be critical for an organism to survive in an environment of rapidly changing nutrients and inflammatory signals. Once we attain a more precise understanding of TRB function in the kidney and other organ systems, it may be possible to develop novel therapeutics that function similar to TRB homologs that can specifically target and modulate signaling cascades, thereby delicately regulating diverse pathophysiological processes.

Acknowledgments

These studies were performed with the support of the Department of Veterans Affairs Merit Award, the University of California San Diego Senate, and UCSD/UCLA NIDDK DRC Pilot and Feasibility Grants P30 DK063491 awarded to Robyn Cunard.

References

J. D. Iglehart and D. P. Silver, “Synthetic lethality: a new direction in cancer-drug development,” The New England Journal of Medicine, vol. 361, no. 2, pp. 189–191, 2009.
View at: Publisher Site | Google Scholar
J. V. Bonventre and L. Yang, “Cellular pathophysiology of ischemic acute kidney injury,” Journal of Clinical Investigation, vol. 121, no. 11, pp. 4210–4221, 2011.
View at: Publisher Site | Google Scholar
R. Bellomo, J. A. Kellum, and C. Ronco, “Acute kidney injury,” The Lancet, vol. 380, no. 9843, pp. 756–766, 2012.
View at: Google Scholar
A. Zarjou and A. Agarwal, “Sepsis and acute kidney injury,” Journal of the American Society of Nephrology, vol. 22, no. 6, pp. 999–1006, 2011.
View at: Publisher Site | Google Scholar
J. Wada and H. Makino, “Inflammation and the pathogenesis of diabetic nephropathy,” Clinical Science, vol. 124, no. 3, pp. 139–152, 2013.
View at: Google Scholar
D. Noone and C. Licht, “Chronic kidney disease: a new look at pathogenetic mechanisms and treatment options,” Pediatric Nephrology, 2013.
View at: Publisher Site | Google Scholar
A. V. Cybulsky, “The intersecting roles of endoplasmic reticulum stress, ubiquitinproteasome system, and autophagy in the pathogenesis of proteinuric kidney disease,” Kidney International, vol. 84, no. 1, pp. 25–33, 2013.
View at: Google Scholar
L. J. Hale and R. J. Coward, “Insulin signalling to the kidney in health and disease,” Clinical Science, vol. 124, no. 6, pp. 351–370, 2013.
View at: Google Scholar
W. Lieberthal and J. S. Levine, “Mammalian target of rapamycin and the kidney. I. The signaling pathway,” The American Journal of Physiology, vol. 303, no. 1, pp. F1–F10, 2012.
View at: Google Scholar
T. C. Seher and M. Leptin, “Tribbles, a cell-cycle brake that coordinates proliferation and morphogenesis during Drosophila gastrulation,” Current Biology, vol. 10, no. 11, pp. 623–629, 2000.
View at: Publisher Site | Google Scholar
J. Mata, S. Curado, A. Ephrussi, and P. Rorth, “Tribbles coordinates mitosis and morphogenesis in Drosophila by regulating string/CDC25 proteolysis,” Cell, vol. 101, no. 5, pp. 511–522, 2000.
View at: Google Scholar
J. Grosshans and E. Wieschaus, “A genetic link between morphogenesis and cell division during formation of the ventral furrow in Drosophila,” Cell, vol. 101, no. 5, pp. 523–531, 2000.
View at: Google Scholar
L. A. Johnston, “Cell cycle: the trouble with tribbles,” Current Biology, vol. 10, no. 13, pp. R502–R504, 2000.
View at: Publisher Site | Google Scholar
P. Rørth, K. Szabo, and G. Texido, “The level of C/EBP protein is critical for cell migration during Drosophila oogenesis and is tightly controlled by regulated degradation,” Molecular Cell, vol. 6, no. 1, pp. 23–30, 2000.
View at: Google Scholar
V. Masoner, R. Das, L. Pence et al., “The kinase domain of Drosophila Tribbles is required for turnover of fly C/EBP during cell migration,” Developmental Biology, vol. 375, no. 1, pp. 33–44, 2013.
View at: Google Scholar
T. Duncan and T. T. Su, “Embryogenesis: coordinating cell division with gastrulation,” Current Biology, vol. 14, no. 8, pp. R305–R307, 2004.
View at: Publisher Site | Google Scholar
P. Fichelson and M. Gho, “Mother-daughter precursor cell fate transformation after Cdc2 down-regulation in the Drosophila bristle lineage,” Developmental Biology, vol. 276, no. 2, pp. 367–377, 2004.
View at: Publisher Site | Google Scholar
L. L. Dobens Jr. and S. Bouyain, “Developmental roles of tribbles protein family members,” Developmental Dynamics, vol. 241, no. 8, pp. 1239–1248, 2012.
View at: Google Scholar
H. LaFerriere, D. J. Guarnieri, D. Sitaraman, S. Diegelmann, U. Heberlein, and T. Zars, “Genetic dissociation of ethanol sensitivity and memory formation in Drosophila melanogaster,” Genetics, vol. 178, no. 4, pp. 1895–1902, 2008.
View at: Publisher Site | Google Scholar
Y. Saka and J. C. Smith, “A Xenopus tribbles orthologue is required for the progression of mitosis and for development of the nervous system,” Developmental Biology, vol. 273, no. 2, pp. 210–225, 2004.
View at: Publisher Site | Google Scholar
N. Pujol, S. Cypowyj, K. Ziegler et al., “Distinct innate immune responses to infection and wounding in the C. elegans epidermis,” Current Biology, vol. 18, no. 7, pp. 481–489, 2008.
View at: Publisher Site | Google Scholar
K. Ziegler, C. L. Kurz, S. Cypowyj et al., “Antifungal innate immunity in C. elegans: PKCδ links G protein signaling and a conserved p38 MAPK cascade,” Cell Host and Microbe, vol. 5, no. 4, pp. 341–352, 2009.
View at: Publisher Site | Google Scholar
C. Couillault, P. Fourquet, M. Pophillat, and J. J. Ewbank, “A UPR-independent infection-specific role for a BiP/GRP78 protein in the control of antimicrobial peptide expression in C. elegans epidermis,” Virulence, vol. 3, no. 3, pp. 299–308, 2012.
View at: Google Scholar
F. Wilkin, N. Suarez-Huerta, B. Robaye et al., “Characterization of a phosphoprotein whose mRNA is regulated by the mitogenic pathways in dog thyroid cells,” European Journal of Biochemistry, vol. 248, no. 3, pp. 660–668, 1997.
View at: Google Scholar
F. Wilkin, V. Savonet, A. Radulescu, J. Petermans, J. E. Dumont, and C. Maenhaut, “Identification and characterization of novel genes modulated in the thyroid of dogs treated with methimazole and propylthiouracil,” Journal of Biological Chemistry, vol. 271, no. 45, pp. 28451–28457, 1996.
View at: Publisher Site | Google Scholar
K. Mayumi-Matsuda, S. Kojima, H. Suzuki, and T. Sakata, “Identification of a novel kinase-like gene induced during neuronal cell death,” Biochemical and Biophysical Research Communications, vol. 258, no. 2, pp. 260–264, 1999.
View at: Publisher Site | Google Scholar
M. Wu, L.-G. Xu, Z. Zhai, and H.-B. Shu, “SINK is a p65-interacting negative regulator of NF-κB-dependent transcription,” Journal of Biological Chemistry, vol. 278, no. 29, pp. 27072–27079, 2003.
View at: Publisher Site | Google Scholar
A. J. Bowers, S. Scully, and J. F. Boylan, “SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia,” Oncogene, vol. 22, no. 18, pp. 2823–2835, 2003.
View at: Publisher Site | Google Scholar
K. Tang, R. L. Finley Jr., D. Nie, and K. V. Honn, “Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening,” Biochemistry, vol. 39, no. 12, pp. 3185–3191, 2000.
View at: Publisher Site | Google Scholar
T. Yokoyama and T. Nakamura, “Tribbles in disease: signaling pathways important for cellular function and neoplastic transformation,” Cancer Science, vol. 102, no. 6, pp. 1115–1122, 2011.
View at: Publisher Site | Google Scholar
S. K. Hanks and T. Hunter, “The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification,” The FASEB Journal, vol. 9, no. 8, pp. 576–596, 1995.
View at: Google Scholar
Z. Hegedus, A. Czibula, and E. Kiss-Toth, “Tribbles: a family of kinase-like proteins with potent signalling regulatory function,” Cellular Signalling, vol. 19, no. 2, pp. 238–250, 2007.
View at: Publisher Site | Google Scholar
J. Boudeau, D. Miranda-Saavedra, G. J. Barton, and D. R. Alessi, “Emerging roles of pseudokinases,” Trends in Cell Biology, vol. 16, no. 9, pp. 443–452, 2006.
View at: Publisher Site | Google Scholar
A. Remenyi, M. C. Good, and W. A. Lim, “Docking interactions in protein kinase and phosphatase networks,” Current Opinion in Structural Biology, vol. 16, no. 6, pp. 676–685, 2006.
View at: Google Scholar
E. Kiss-Toth, S. M. Bagstaff, H. Y. Sung et al., “Human tribbles, a protein family controlling mitogen-activated protein kinase cascades,” Journal of Biological Chemistry, vol. 279, no. 41, pp. 42703–42708, 2004.
View at: Publisher Site | Google Scholar
E. Zeqiraj and D. M. van Aalten, “Pseudokinases-remnants of evolution or key allosteric regulators?” Current Opinion in Structural Biology, vol. 20, no. 6, pp. 772–781, 2010.
View at: Publisher Site | Google Scholar
B.-E. Xu, J. M. English, J. L. Wilsbacher, S. Stippec, E. J. Goldsmith, and M. H. Cobb, “WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II,” Journal of Biological Chemistry, vol. 275, no. 22, pp. 16795–16801, 2000.
View at: Publisher Site | Google Scholar
F. H. Wilson, S. Disse-Nicodème, K. A. Choate et al., “Human hypertension caused by mutations in WNK kinases,” Science, vol. 293, no. 5532, pp. 1107–1112, 2001.
View at: Publisher Site | Google Scholar
K. Mukherjee, M. Sharma, H. Urlaub et al., “CASK functions as a Mg2+-independent neurexin kinase,” Cell, vol. 133, no. 2, pp. 328–339, 2008.
View at: Publisher Site | Google Scholar
F. Shi, S. E. Telesco, Y. Liu, R. Radhakrishnan, and M. A. Lemmona, “ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 17, pp. 7692–7697, 2010.
View at: Publisher Site | Google Scholar
A. P. Kornev and S. S. Taylor, “Pseudokinases: functional insights gleaned from structure,” Structure, vol. 17, no. 1, pp. 5–7, 2009.
View at: Publisher Site | Google Scholar
L. Qi, J. E. Heredia, J. Y. Altarejos et al., “TRB3 links the E3 ubiquitin ligase COF1 to lipid metabolism,” Science, vol. 312, no. 5781, pp. 1763–1766, 2006.
View at: Publisher Site | Google Scholar
K. Keeshan, W. Bailis, P. H. Dedhia et al., “Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding,” Blood, vol. 116, no. 23, pp. 4948–4957, 2010.
View at: Publisher Site | Google Scholar
T. Yokoyama, Y. Kanno, Y. Yamazaki, T. Takahara, S. Miyata, and T. Nakamura, “Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis,” Blood, vol. 116, no. 15, pp. 2768–2775, 2010.
View at: Publisher Site | Google Scholar
R. K. Humphrey, C. J. Newcomb, S.-M. A. Yu et al., “Mixed lineage kinase-3 stabilizes and functionally cooperates with TRIBBLES-3 to compromise mitochondrial integrity in cytokine-induced death of pancreatic beta cells,” Journal of Biological Chemistry, vol. 285, no. 29, pp. 22426–22436, 2010.
View at: Publisher Site | Google Scholar
N. Ohoka, S. Sakai, K. Onozaki, M. Nakanishi, and H. Hayashi, “Anaphase-promoting complex/cyclosome-cdh1 mediates the ubiquitination and degradation of TRB3,” Biochemical and Biophysical Research Communications, vol. 392, no. 3, pp. 289–294, 2010.
View at: Publisher Site | Google Scholar
M. Imajo and E. Nishida, “Human Tribbles homolog 1 functions as a negative regulator of retinoic acid receptor,” Genes to Cells, vol. 15, no. 10, pp. 1089–1097, 2010.
View at: Publisher Site | Google Scholar
H. Okamoto, E. Latres, R. Liu et al., “Genetic deletion of Trb3, the mammalian Drosophila tribbles homolog, displays normal hepatic insulin signaling and glucose homeostasis,” Diabetes, vol. 56, no. 5, pp. 1350–1356, 2007.
View at: Publisher Site | Google Scholar
J. Ashton-Chess, M. Giral, M. Mengel et al., “Tribbles-1 as a novel biomarker of chronic antibody-mediated rejection,” Journal of the American Society of Nephrology, vol. 19, no. 6, pp. 1116–1127, 2008.
View at: Publisher Site | Google Scholar
A. Ostertag, A. Jones, A. J. Rose et al., “Control of adipose tissue inflammation through TRB1,” Diabetes, vol. 59, no. 8, pp. 1991–2000, 2010.
View at: Publisher Site | Google Scholar
T. Satoh, H. Kidoya, H. Naito et al., “Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages,” Nature, vol. 495, no. 7442, pp. 524–528, 2013.
View at: Google Scholar
E. Selim, J. T. Frkanec, and R. Cunard, “Fibrates upregulate TRB3 in lymphocytes independent of PPARα by augmenting CCAAT/enhancer-binding proteinβ (C/EBPβ) expression,” Molecular Immunology, vol. 44, no. 6, pp. 1218–1229, 2007.
View at: Publisher Site | Google Scholar
E. Morse, J. Schroth, N.-H. You et al., “TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1,” The American Journal of Physiology, vol. 299, no. 5, pp. F965–F972, 2010.
View at: Publisher Site | Google Scholar
J. Liu, X. Wu, J. L. Franklin et al., “Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance,” The American Journal of Physiology, vol. 298, no. 3, pp. E565–E576, 2010.
View at: Publisher Site | Google Scholar
M. Takasato, C. Kobayashi, K. Okabayashi et al., “Trb2, a mouse homolog of tribbles, is dispensable for kidney and mouse development,” Biochemical and Biophysical Research Communications, vol. 373, no. 4, pp. 648–652, 2008.
View at: Publisher Site | Google Scholar
H. Y. Sung, S. E. Francis, N. Arnold et al., “Enhanced macrophage tribbles-1 expression in murine experimental atherosclerosis,” Biology, vol. 1, no. 1, pp. 43–57, 2012.
View at: Google Scholar
N. Ohoka, S. Yoshii, T. Hattori, K. Onozaki, and H. Hayashi, “TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death,” EMBO Journal, vol. 24, no. 6, pp. 1243–1255, 2005.
View at: Publisher Site | Google Scholar
L. V. Sharova, A. A. Sharov, T. Nedorezov, Y. Piao, N. Shaik, and M. S. H. Ko, “Database for mRNA half-life of 19 977 genes obtained by DNA microarray analysis of pluripotent and differentiating mouse embryonic stem cells,” DNA Research, vol. 16, no. 1, pp. 45–58, 2009.
View at: Publisher Site | Google Scholar
Y. Zhou, L. Li, Q. Liu et al., “E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3,” Cellular Signalling, vol. 20, no. 5, pp. 942–948, 2008.
View at: Publisher Site | Google Scholar
K. Shimizu, S. Takahama, Y. Endo, and T. Sawasaki, “Stress-inducible caspase substrate TRB3 promotes nuclear translocation of procaspase-3,” PLoS ONE, vol. 7, no. 8, Article ID e42721, 2012.
View at: Google Scholar
S. Kato and K. Du, “TRB3 modulates C2C12 differentiation by interfering with Akt activation,” Biochemical and Biophysical Research Communications, vol. 353, no. 4, pp. 933–938, 2007.
View at: Publisher Site | Google Scholar
P. Sathyanarayana, A. Dev, J. Fang et al., “EPO receptor circuits for primary erythroblast survival,” Blood, vol. 111, no. 11, pp. 5390–5399, 2008.
View at: Publisher Site | Google Scholar
O. Bezy, C. Vernochet, S. Gesta, S. R. Farmer, and C. R. Kahn, “TRB3 blocks adipocyte differentiation through the inhibition of C/EBPβ transcriptional activity,” Molecular and Cellular Biology, vol. 27, no. 19, pp. 6818–6831, 2007.
View at: Publisher Site | Google Scholar
Y. Takahashi, N. Ohoka, H. Hayashi, and R. Sato, “TRB3 suppresses adipocyte differentiation by negatively regulating PPARγ transcriptional activity,” Journal of Lipid Research, vol. 49, no. 4, pp. 880–892, 2008.
View at: Publisher Site | Google Scholar
M. C. Chan, P. H. Nguyen, B. N. Davis et al., “A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor,” Molecular and Cellular Biology, vol. 27, no. 16, pp. 5776–5789, 2007.
View at: Publisher Site | Google Scholar
D. Örd and T. Örd, “Mouse NIPK interacts with ATF4 and affects its transcriptional activity,” Experimental Cell Research, vol. 286, no. 2, pp. 308–320, 2003.
View at: Publisher Site | Google Scholar
D. Örd and T. Örd, “Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions,” Biochemical and Biophysical Research Communications, vol. 330, no. 1, pp. 210–218, 2005.
View at: Publisher Site | Google Scholar
C. W. Liew, J. Bochenski, D. Kawamori et al., “The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells,” Journal of Clinical Investigation, vol. 120, no. 8, pp. 2876–2888, 2010.
View at: Publisher Site | Google Scholar
T. Naiki, E. Saijou, Y. Miyaoka, K. Sekine, and A. Miyajima, “TRB2, a mouse tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBP,” Journal of Biological Chemistry, vol. 282, no. 33, pp. 24075–24082, 2007.
View at: Publisher Site | Google Scholar
K. Keeshan, Y. He, B. J. Wouters et al., “Tribbles homolog 2 inactivates C/EBPα and causes acute myelogenous leukemia,” Cancer Cell, vol. 10, no. 5, pp. 401–411, 2006.
View at: Publisher Site | Google Scholar
P. H. Dedhia, K. Keeshan, S. Uljon et al., “Differential ability of Tribbles family members to promote degradation of C/EBPα and induce acute myelogenous leukemia,” Blood, vol. 116, no. 8, pp. 1321–1328, 2010.
View at: Publisher Site | Google Scholar
M. Matsumoto, S. Han, T. Kitamura, and D. Accili, “Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism,” Journal of Clinical Investigation, vol. 116, no. 9, pp. 2464–2472, 2006.
View at: Publisher Site | Google Scholar
F. Zanella, O. Renner, B. García et al., “Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells,” Oncogene, vol. 29, no. 20, pp. 2973–2982, 2010.
View at: Publisher Site | Google Scholar
E. Dugast, E. Kiss-Toth, L. Docherty et al., “Identification of tribbles-1 as a novel binding partner of Foxp3 in regulatory T cells,” Journal of Biological Chemistry, vol. 288, no. 14, pp. 10051–10060, 2013.
View at: Google Scholar
D. Weismann, D. M. Erion, I. Ignatova-Todorava et al., “Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance,” Diabetologia, vol. 54, no. 4, pp. 935–944, 2011.
View at: Publisher Site | Google Scholar
C. D. Dummer, V. N. Carpio, L. F. S. Gonçalves, R. C. Manfro, and F. V. Veronese, “FOXP3+ regulatory T cells: from suppression of rejection to induction of renal allograft tolerance,” Transplant Immunology, vol. 26, no. 1, pp. 1–10, 2012.
View at: Publisher Site | Google Scholar
X. C. Li and L. A. Turka, “An update on regulatory T cells in transplant tolerance and rejection,” Nature Reviews Nephrology, vol. 6, no. 10, pp. 577–583, 2010.
View at: Publisher Site | Google Scholar
Y. S. Hye, H. Guan, A. Czibula et al., “Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways,” Journal of Biological Chemistry, vol. 282, no. 25, pp. 18379–18387, 2007.
View at: Publisher Site | Google Scholar
R. Burkhardt, S.-A. Toh, W. R. Lagor et al., “Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice,” Journal of Clinical Investigation, vol. 120, no. 12, pp. 4410–4414, 2010.
View at: Publisher Site | Google Scholar
A. Varbo, M. Benn, A. Tybjærg-Hansen, P. Grande, and B. G. Nordestgaard, “TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 2, pp. 451–457, 2011.
View at: Publisher Site | Google Scholar
J. C. Chambers, W. Zhang, J. Sehmi et al., “Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma,” Nature Genetics, vol. 43, no. 11, pp. 1131–1138, 2011.
View at: Publisher Site | Google Scholar
F. O. Martinez, L. Helming, and S. Gordon, “Alternative activation of macrophages: an immunologic functional perspective,” Annual Review of Immunology, vol. 27, pp. 451–483, 2009.
View at: Publisher Site | Google Scholar
S. K. Biswas and A. Mantovani, “Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm,” Nature Immunology, vol. 11, no. 10, pp. 889–896, 2010.
View at: Publisher Site | Google Scholar
C. D. Mills, “M1 and M2 macrophages: oracles of health and disease,” Critical Reviews in Immunology, vol. 32, no. 6, pp. 463–488, 2012.
View at: Google Scholar
M. Yamamoto, S. Uematsu, T. Okamoto et al., “Enhanced TLR-mediated NF-IL6-dependent gene expression by Trib1 deficiency,” Journal of Experimental Medicine, vol. 204, no. 9, pp. 2233–2239, 2007.
View at: Publisher Site | Google Scholar
Y. H. Liu, K. A. Tan, I. W. Morrison, J. R. Lamb, and D. J. Argyle, “Macrophage migration is controlled by Tribbles 1 through the interaction between C/EBPbeta and TNF-alpha,” Veterinary Immunology and Immunopathology, vol. 155, no. 1-2, pp. 67–75, 2013.
View at: Google Scholar
C. S. Marie, H. P. Verkerke, S. N. Paul, A. J. Mackey, and W. A. Petri Jr., “Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism,” Infection and Immunity, vol. 80, no. 5, pp. 1934–1943, 2012.
View at: Google Scholar
O. Nov, A. Kohl, E. C. Lewis et al., “Interleukin-1β may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation,” Endocrinology, vol. 151, no. 9, pp. 4247–4256, 2010.
View at: Publisher Site | Google Scholar
M. S. Wiedemann, S. Wueest, F. Item, E. J. Schoenle, and D. Konrad, “Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance,” The American Journal of Physiology, vol. 305, no. 3, pp. E388–E395, 2013.
View at: Google Scholar
M. Takasato, K. Osafune, Y. Matsumoto et al., “Identification of kidney mesenchymal genes by a combination of microarray analysis and Sall1-GFP knockin mice,” Mechanisms of Development, vol. 121, no. 6, pp. 547–557, 2004.
View at: Publisher Site | Google Scholar
K.-R. Lin, S.-F. Lee, C.-M. Hung, C.-L. Li, H.-F. Yang-Yen, and J. J. Y. Yen, “Survival factor withdrawal-induced apoptosis of TF-1 cells involves a TRB2-Mcl-1 axis-dependent pathway,” Journal of Biological Chemistry, vol. 282, no. 30, pp. 21962–21972, 2007.
View at: Publisher Site | Google Scholar
K. Eder, H. Guan, H. Y. Sung et al., “Tribbles-2 is a novel regulator of inflammatory activation of monocytes,” International Immunology, vol. 20, no. 12, pp. 1543–1550, 2008.
View at: Publisher Site | Google Scholar
J. Deng, C. H. James, L. Patel et al., “Human tribbles homologue 2 is expressed in unstable regions of carotid plaques and regulates macrophage IL-10 in vitro,” Clinical Science, vol. 116, no. 3, pp. 241–248, 2009.
View at: Publisher Site | Google Scholar
C. H. Kuo, K. Morohoshi, C. C. Aye, R. B. Garoon, A. Collins, and S. J. Ono, “The role of TRB3 in mast cells sensitized with monomeric IgE,” Experimental and Molecular Pathology, vol. 93, no. 3, pp. 408–415, 2012.
View at: Google Scholar
K. Du, S. Herzig, R. N. Kulkarni, and M. Montminy, “TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver,” Science, vol. 300, no. 5625, pp. 1574–1577, 2003.
View at: Publisher Site | Google Scholar
S.-H. Koo, H. Satoh, S. Herzig et al., “PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3,” Nature Medicine, vol. 10, no. 5, pp. 530–534, 2004.
View at: Publisher Site | Google Scholar
P. B. Iynedjian, “Lack of evidence for a role of TRB3/NIPK as an inhibitor of PKB-mediated insulin signalling in primary hepatocytes,” Biochemical Journal, vol. 386, no. 1, pp. 113–118, 2005.
View at: Publisher Site | Google Scholar
R. Matsushima, N. Harada, N. J. G. Webster, Y. M. Tsutsumi, and Y. Nakaya, “Effect of TRB3 on insulin and nutrient-stimulated hepatic p70 S6 kinase activity,” Journal of Biological Chemistry, vol. 281, no. 40, pp. 29719–29729, 2006.
View at: Publisher Site | Google Scholar
J. Liu, W. Zhang, G. C. Chuang et al., “Role of TRIB3 in regulation of insulin sensitivity and nutrient metabolism during short-term fasting and nutrient excess,” The American Journal of Physiology, vol. 303, no. 7, pp. E908–E916, 2012.
View at: Google Scholar
H.-J. Koh, D. E. Arnolds, N. Fujii et al., “Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3,” Molecular and Cellular Biology, vol. 26, no. 22, pp. 8217–8227, 2006.
View at: Publisher Site | Google Scholar
A. R. Saltiel, “Putting the brakes on insulin signaling,” The New England Journal of Medicine, vol. 349, no. 26, pp. 2560–2562, 2003.
View at: Publisher Site | Google Scholar
X.-P. Bi, H.-W. Tan, S.-S. Xing et al., “Overexpression of TRB3 gene in adipose tissue of rats with high fructose-induced metabolic syndrome,” Endocrine Journal, vol. 55, no. 4, pp. 747–752, 2008.
View at: Publisher Site | Google Scholar
T. Örd, D. Örd, S. Kuuse, M. Plaas, and T. Örd, “Trib3 is regulated by IL-3 and affects bone marrow-derived mast cell survival and function,” Cellular Immunology, vol. 280, no. 1, pp. 68–75, 2012.
View at: Google Scholar
Z.-H. Wang, Y.-Y. Shang, S. Zhang et al., “Silence of TRIB3 suppresses atherosclerosis and stabilizes plaques in diabetic ApoE -/- LDL receptor -/- mice,” Diabetes, vol. 61, no. 2, pp. 463–473, 2012.
View at: Publisher Site | Google Scholar
Y. Ti, G.-L. Xie, Z.-H. Wang et al., “TRB3 gene silencing alleviates diabetic cardiomyopathy in a type 2 diabetic rat model,” Diabetes, vol. 60, no. 11, pp. 2963–2974, 2011.
View at: Publisher Site | Google Scholar
J. Avery, S. Etzion, B. J. Debosch et al., “TRB3 function in cardiac endoplasmic reticulum stress,” Circulation Research, vol. 106, no. 9, pp. 1516–1523, 2010.
View at: Publisher Site | Google Scholar
M. Salazar, A. Carracedo, Í. J. Salanueva et al., “Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells,” Journal of Clinical Investigation, vol. 119, no. 5, pp. 1359–1372, 2009.
View at: Publisher Site | Google Scholar
Y.-Y. Shang, Z.-H. Wang, L.-P. Zhang et al., “TRB3, upregulated by ox-LDL, mediates human monocyte-derived macrophage apoptosis,” FEBS Journal, vol. 276, no. 10, pp. 2752–2761, 2009.
View at: Publisher Site | Google Scholar
J. D. Cravero, C. S. Carlson, H.-J. Im, R. R. Yammani, D. Long, and R. F. Loeser, “Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin-like growth factor 1-mediated cell survival and proteoglycan synthesis,” Arthritis and Rheumatism, vol. 60, no. 2, pp. 492–500, 2009.
View at: Publisher Site | Google Scholar
D. Örd, K. Meerits, and T. Örd, “TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4,” Experimental Cell Research, vol. 313, no. 16, pp. 3556–3567, 2007.
View at: Publisher Site | Google Scholar
R. Schwarzer, S. Dames, D. Tondera, A. Klippel, and J. Kaufmann, “TRB3 is a PI 3-kinase dependent indicator for nutrient starvation,” Cellular Signalling, vol. 18, no. 6, pp. 899–909, 2006.
View at: Publisher Site | Google Scholar
V. Foe, G. Odell, and B. Edgar, Eds., Mitosis and Morphogenesis in the Drosophila Embry: Point and Counter Point, Cold Spring Harbor Laboratory Press, New York, NY, USA, 1993.
J. Pines and T. Hunter, “Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34(cdc2),” Cell, vol. 58, no. 5, pp. 833–846, 1989.
View at: Google Scholar
R. Boutros, V. Lobjois, and B. Ducommun, “CDC25 phosphatases in cancer cells: key players? Good targets?” Nature Reviews Cancer, vol. 7, no. 7, pp. 495–507, 2007.
View at: Publisher Site | Google Scholar
S. Sakai, N. Ohoka, K. Onozaki, M. Kitagawa, M. Nakanishi, and H. Hayashi, “Dual mode of regulation of cell division cycle 25 a protein by TRB3,” Biological and Pharmaceutical Bulletin, vol. 33, no. 7, pp. 1112–1116, 2010.
View at: Publisher Site | Google Scholar
E. Morse, E. Selim, and R. Cunard, “PPARα ligands cause lymphocyte depletion and cell cycle block and this is associated with augmented TRB3 and reduced Cyclin B1 expression,” Molecular Immunology, vol. 46, no. 16, pp. 3454–3461, 2009.
View at: Publisher Site | Google Scholar
T. Zou, W.-J. Liu, S.-D. Li, W. Zhou, J.-F. Yang, and C.-G. Zou, “TRB3 mediates homocysteine-induced inhibition of endothelial cell proliferation,” Journal of Cellular Physiology, vol. 226, no. 11, pp. 2782–2789, 2011.
View at: Publisher Site | Google Scholar
E. Kiss-Toth, D. H. Wyllie, K. Holland et al., “Functional mapping and identification of novel regulators for the Toll/Interleukin-1 signalling network by transcription expression cloning,” Cellular Signalling, vol. 18, no. 2, pp. 202–214, 2006.
View at: Publisher Site | Google Scholar
S. M. Smith, A. P. Moran, S. P. Duggan et al., “Tribbles 3: a novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide,” Journal of Immunology, vol. 186, no. 4, pp. 2462–2471, 2011.
View at: Publisher Site | Google Scholar
C. Jousse, C. Deval, A.-C. Maurin et al., “TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway,” Journal of Biological Chemistry, vol. 282, no. 21, pp. 15851–15861, 2007.
View at: Publisher Site | Google Scholar
V. Carraro, A.-C. Maurin, S. Lambert-Langlais et al., “Amino acid availability controls TRB3 transcription in liver through the GCN2/EIF2a/ATF4 pathway,” PLoS ONE, vol. 5, no. 12, Article ID e15716, 2010.
View at: Publisher Site | Google Scholar
S. Z. Y. Wasef, K. A. Robinson, M. N. Berkaw, and M. G. Buse, “Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes,” The American Journal of Physiology, vol. 291, no. 6, pp. E1274–E1280, 2006.
View at: Publisher Site | Google Scholar
L. He, F. A. Simmen, H. M. Mehendale, M. J. J. Ronis, and T. M. Badger, “Chronic ethanol intake impairs insulin signaling in rats by disrupting Akt association with the cell membrane: role of TRB3 in inhibition of Akt/protein kinase B activation,” Journal of Biological Chemistry, vol. 281, no. 16, pp. 11126–11134, 2006.
View at: Publisher Site | Google Scholar
R. S. Seelan, A. Khalyfa, J. Lakshmanan, M. F. Casanova, and R. N. Parthasarathy, “Deciphering the lithium transcriptome: microarray profiling of lithium-modulated gene expression in human neuronal cells,” Neuroscience, vol. 151, no. 4, pp. 1184–1197, 2008.
View at: Publisher Site | Google Scholar
C. A. Corcoran, X. Luo, Q. He, C. Jiang, Y. Huang, and M. S. Sheikh, “Genotoxic and endoplasmic reticulum stresses differentially regulate TRB3 expression,” Cancer Biology and Therapy, vol. 4, no. 10, pp. 1063–1067, 2005.
View at: Google Scholar
X.-H. Yao and B. L. Grégoire Nyomba, “Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring,” The American Journal of Physiology, vol. 294, no. 6, pp. R1797–R1806, 2008.
View at: Publisher Site | Google Scholar
M. Hanada, J. Feng, and B. A. Hemmings, “Structure, regulation and function of PKB/AKT: a major therapeutic target,” Biochimica et Biophysica Acta, vol. 1697, no. 1-2, pp. 3–16, 2004.
View at: Publisher Site | Google Scholar
D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini, “Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex,” Science, vol. 307, no. 5712, pp. 1098–1101, 2005.
View at: Publisher Site | Google Scholar
V. Facchinetti, W. Ouyang, H. Wei et al., “The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C,” EMBO Journal, vol. 27, no. 14, pp. 1932–1943, 2008.
View at: Publisher Site | Google Scholar
D. Feliers, S. Duraisamy, J. L. Faulkner et al., “Activation of renal signaling pathways in db/db mice with type 2 diabetes,” Kidney International, vol. 60, no. 2, pp. 495–504, 2001.
View at: Publisher Site | Google Scholar
Y. Gorin, K. Block, J. Hernandez et al., “Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney,” Journal of Biological Chemistry, vol. 280, no. 47, pp. 39616–39626, 2005.
View at: Publisher Site | Google Scholar
N. Lloberas, J. M. Cruzado, M. Franquesa et al., “Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats,” Journal of the American Society of Nephrology, vol. 17, no. 5, pp. 1395–1404, 2006.
View at: Publisher Site | Google Scholar
Y. Gorin, N.-H. Kim, D. Feliers, B. Bhandari, G. G. Choudhury, and H. E. Abboud, “Angiotensin II activates Akt/protein kinase B by an arachidonic acid/redox-dependent pathway and independent of phosphoinositide 3-kinase,” The FASEB Journal, vol. 15, no. 11, pp. 1909–1920, 2001.
View at: Publisher Site | Google Scholar
K. Nagai, T. Matsubara, A. Mima et al., “Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy,” Kidney International, vol. 68, no. 2, pp. 552–561, 2005.
View at: Publisher Site | Google Scholar
S. Chen, S. Mukherjee, C. Chakraborty, and S. Chakrabarti, “High glucose-induced, endothelin-dependent fibronectin synthesis is mediated via NF-κB and AP-1,” The American Journal of Physiology, vol. 284, no. 2, pp. C263–C272, 2003.
View at: Google Scholar
J. Zhu, N. Sun, L. Aoudjit et al., “Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes,” Kidney International, vol. 73, no. 5, pp. 556–566, 2008.
View at: Publisher Site | Google Scholar
T. Tejada, P. Catanuto, A. Ijaz et al., “Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death,” Kidney International, vol. 73, no. 12, pp. 1385–1393, 2008.
View at: Publisher Site | Google Scholar
J. Vassiliadis, C. Bracken, D. Matthews, S. O'Brien, S. Schiavi, and S. Wawersik, “Calcium mediates glomerular filtration through calcineurin and mTORC2/Akt signaling,” Journal of the American Society of Nephrology, vol. 22, no. 8, pp. 1453–1461, 2011.
View at: Publisher Site | Google Scholar
S. K. Lim and S. H. Park, “The high glucose-induced stimulation of B1R and B2R expression via CB(1)R activation is involved in rat podocyte apoptosis,” Life Sciences, vol. 91, no. 19-20, pp. 895–906, 2012.
View at: Google Scholar
Y. Takano, K. Yamauchi, K. Hayakawa et al., “Transcriptional suppression of nephrin in podocytes by macrophages: roles of inflammatory cytokines and involvement of the PI3K/Akt pathway,” FEBS Letters, vol. 581, no. 3, pp. 421–426, 2007.
View at: Publisher Site | Google Scholar
E. Jacinto, V. Facchinetti, D. Liu et al., “SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity,” Cell, vol. 127, no. 1, pp. 125–137, 2006.
View at: Publisher Site | Google Scholar
S.-X. Tan, Y. Ng, C. C. Meoli et al., “Amplification and demultiplexing in insulin-regulated Akt protein kinase pathway in adipocytes,” Journal of Biological Chemistry, vol. 287, no. 9, pp. 6128–6138, 2012.
View at: Publisher Site | Google Scholar
J. Ding, S. Kato, and K. Du, “PI3K activates negative and positive signals to regulate TRB3 expression in hepatic cells,” Experimental Cell Research, vol. 314, no. 7, pp. 1566–1574, 2008.
View at: Publisher Site | Google Scholar
K. K. Y. Cheng, M. A. Iglesias, K. S. L. Lam et al., “APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice,” Cell Metabolism, vol. 9, no. 5, pp. 417–427, 2009.
View at: Publisher Site | Google Scholar
E. A. Borsting, S. Patel, A. E. Declèves et al., “TRB3, an endoplasmic reticulum stress-associated protein, binds to rictor and attenuates mTORC2 signaling and inflammation in the diabetic kidney,” In Review.
View at: Google Scholar
M. Salazar, M. Lorente, E. Garcia-Taboada et al., “The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action,” Biochimica et Biophysica Acta, vol. 1831, no. 10, pp. 1573–1578, 2013.
View at: Google Scholar
D. Accili and K. C. Arden, “FoxOs at the crossroads of cellular metabolism, differentiation, and transformation,” Cell, vol. 117, no. 4, pp. 421–426, 2004.
View at: Publisher Site | Google Scholar
G. Rena, G. Shaodong, S. C. Cichy, T. G. Unterman, and P. Cohen, “Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B,” Journal of Biological Chemistry, vol. 274, no. 24, pp. 17179–17183, 1999.
View at: Publisher Site | Google Scholar
H. Matsuzaki, H. Daitoku, M. Hatta, K. Tanaka, and A. Fukamizu, “Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 20, pp. 11285–11290, 2003.
View at: Publisher Site | Google Scholar
G. Tzivion, M. Dobson, and G. Ramakrishnan, “FoxO transcription factors: regulation by AKT and 14-3-3 proteins,” Biochimica et Biophysica Acta, vol. 1813, no. 11, pp. 1938–1945, 2011.
View at: Publisher Site | Google Scholar
K. B. Grandinetti, T. A. Stevens, S. Ha et al., “Overexpression of TRIB2 in human lung cancers contributes to tumorigenesis through downregulation of C/EBPα,” Oncogene, vol. 30, no. 30, pp. 3328–3335, 2011.
View at: Publisher Site | Google Scholar
T. Rzymski, A. Paantjens, J. Bod, and A. L. Harris, “Multiple pathways are involved in the anoxia response of SKIP3 including HuR-regulated RNA stability, NF-κB and ATF4,” Oncogene, vol. 27, no. 33, pp. 4532–4543, 2008.
View at: Publisher Site | Google Scholar
F. Hua, R. Mu, J. Liu et al., “TRB3 interacts with SMAD3 promoting tumor cell migration and invasion,” Journal of Cell Science, vol. 124, no. 19, pp. 3235–3246, 2011.
View at: Publisher Site | Google Scholar
J. Xu, S. Lv, Y. Qin et al., “TRB3 interacts with CtIP and is overexpressed in certain cancers,” Biochimica et Biophysica Acta, vol. 1770, no. 2, pp. 273–278, 2007.
View at: Publisher Site | Google Scholar
Y. Sirin and K. Susztak, “Notch in the kidney: development and disease,” Journal of Pathology, vol. 226, no. 2, pp. 394–403, 2012.
View at: Publisher Site | Google Scholar
J. Izrailit, H. K. Berman, A. Datti, J. L. Wrana, and M. Reedijk, “High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFbeta pathways as fundamental Notch regulators in breast cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 5, pp. 1714–1719, 2013.
View at: Google Scholar
H. Zhou, Y. Luo, J. H. Chen et al., “Knockdown of TRB3 induces apoptosis in human lung adenocarcinoma cells through regulation of Notch 1 expression,” Molecular Medicine Reports, vol. 8, no. 1, pp. 47–52, 2013.
View at: Google Scholar
M. Wennemers, J. Bussink, N. Grebenchtchikov, F. C. G. J. Sweep, and P. N. Span, “TRIB3 protein denotes a good prognosis in breast cancer patients and is associated with hypoxia sensitivity,” Radiotherapy and Oncology, vol. 101, no. 1, pp. 198–202, 2011.
View at: Publisher Site | Google Scholar
M. Wennemers, J. Bussink, B. Scheijen et al., “Tribbles homolog 3 denotes a poor prognosis in breast cancer and is involved in hypoxia response,” Breast Cancer Research, vol. 13, no. 4, article R82, 2011.
View at: Publisher Site | Google Scholar
M. Wennemers, J. Bussink, T. van den Beucken, F. C. Sweep, and P. N. Span, “Regulation of TRIB3 mRNA and protein in breast cancer,” PLoS ONE, vol. 7, no. 11, Article ID e49439, 2012.
View at: Google Scholar
N. Miyoshi, H. Ishii, K. Mimori et al., “Abnormal expression of TRIB3 in colorectal cancer: a novel marker for prognosis,” British Journal of Cancer, vol. 101, no. 10, pp. 1664–1670, 2009.
View at: Publisher Site | Google Scholar
D. Vara, M. Salazar, N. Olea-Herrero, M. Guzmán, G. Velasco, and I. Díaz-Laviada, “Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy,” Cell Death and Differentiation, vol. 18, no. 7, pp. 1099–1111, 2011.
View at: Publisher Site | Google Scholar
N. Lampiasi, A. Azzolina, N. D'Alessandro et al., “Antitumor effects of dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, in human liver cancer cells are mediated through a reactive oxygen species-dependent mechanism,” Molecular Pharmacology, vol. 76, no. 2, pp. 290–300, 2009.
View at: Publisher Site | Google Scholar
M. M. Aynaud, R. Suspene, P. O. Vidalain et al., “Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A,” Journal of Biological Chemistry, vol. 287, no. 46, pp. 39182–39192, 2012.
View at: Google Scholar
B. Röthlisberger, M. Heizmann, M. J. Bargetzi, and A. R. Huber, “TRIB1 overexpression in acute myeloid leukemia,” Cancer Genetics and Cytogenetics, vol. 176, no. 1, pp. 58–60, 2007.
View at: Publisher Site | Google Scholar
G. Jin, Y. Yamazaki, M. Takuwa et al., “Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis,” Blood, vol. 109, no. 9, pp. 3998–4005, 2007.
View at: Publisher Site | Google Scholar
T. Yokoyama, T. Toki, Y. Aoki et al., “Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia,” Blood, vol. 119, no. 11, pp. 2608–2611, 2012.
View at: Publisher Site | Google Scholar
D. C. Gilby, H. Y. Sung, P. R. Winship, A. C. Goodeve, J. T. Reilly, and E. Kiss-Toth, “Tribbles-1 and -2 are tumour suppressors, down-regulated in human acute myeloid leukaemia,” Immunology Letters, vol. 130, no. 1-2, pp. 115–124, 2010.
View at: Publisher Site | Google Scholar
M. M. Hannon, F. Lohan, Y. Erbilgin et al., “Elevated TRIB2 with NOTCH1 activation in paediatric/adult TALL,” British Journal of Haematology, vol. 158, no. 5, pp. 626–634, 2012.
View at: Google Scholar
P. Johansson, L. Eisele, L. Klein-Hitpass et al., “Percentage of smudge cells determined on routine blood smears is a novel prognostic factor in chronic lymphocytic leukemia,” Leukemia Research, vol. 34, no. 7, pp. 892–898, 2010.
View at: Publisher Site | Google Scholar
K. L. Liang, L. Rishi, and K. Keeshan, “Tribbles in acute leukemia,” Blood, vol. 121, no. 21, pp. 4265–4270, 2013.
View at: Google Scholar
L. G. Puskas, F. Juhasz, A. Zarva, L. Hackler Jr., and N. R. Farid, “Gene profiling identifies genes specific for well-differentiated epithelial thyroid tumors,” Cellular and Molecular Biology, vol. 51, no. 2, pp. 177–186, 2005.
View at: Google Scholar
M.-L. Puiffe, C. le Page, A. Filali-Mouhim et al., “Characterization of ovarian cancer ascites on cell invasion, proliferation, spheroid formation, and gene expression in an in vitro model of epithelial ovarian cancer,” Neoplasia, vol. 9, no. 10, pp. 820–829, 2007.
View at: Publisher Site | Google Scholar
E. Puigdecanet, B. Espinet, J. J. Lozano et al., “Gene expression profiling distinguishes JAK2V617F-negative from JAK2V617F-positive patients in essential thrombocythemia,” Leukemia, vol. 22, no. 7, pp. 1368–1376, 2008.
View at: Publisher Site | Google Scholar
J. Wang, J. S. Park, Y. Wei et al., “TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPalpha function,” Molecular Cell, vol. 51, no. 2, pp. 211–225, 2013.
View at: Google Scholar
S. Prudente, M. L. Hribal, E. Flex et al., “The functional Q84R polymorphism of mammalian tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in Caucasians from Italy,” Diabetes, vol. 54, no. 9, pp. 2807–2811, 2005.
View at: Publisher Site | Google Scholar
H.-P. Gong, Z.-H. Wang, H. Jiang et al., “TRIB3 functional Q84R polymorphism is a risk factor for metabolic syndrome and carotid atherosclerosis,” Diabetes Care, vol. 32, no. 7, pp. 1311–1313, 2009.
View at: Publisher Site | Google Scholar
G. Formoso, P. di Tomo, F. Andreozzi et al., “The TRIB3 R84 variant is associated with increased carotid intimamedia thickness in vivo and with enhanced MAPK signalling in human endothelial cells,” Cardiovascular Research, vol. 89, no. 1, pp. 184–192, 2011.
View at: Publisher Site | Google Scholar
F. Andreozzi, G. Formoso, S. Prudente et al., “TRIB3 R84 variant is associated with impaired insulin-mediated nitric oxide production in human endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 7, pp. 1355–1360, 2008.
View at: Publisher Site | Google Scholar
S. Prudente, G. Sesti, A. Pandolfi, F. Andreozzi, A. Consoli, and V. Trischitta, “The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases,” Endocrine Reviews, vol. 33, no. 4, pp. 526–546, 2012.
View at: Google Scholar
H. Oberkofler, A. Pfeifenberger, S. Soyal et al., “Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans,” Diabetologia, vol. 53, no. 9, pp. 1971–1975, 2010.
View at: Publisher Site | Google Scholar
I. Kouroumichakis, N. Papanas, P. Zarogoulidis, V. Liakopoulos, E. Maltezos, and D. P. Mikhailidis, “Fibrates: therapeutic potential for diabetic nephropathy?” European Journal of Internal Medicine, vol. 23, no. 4, pp. 309–316, 2012.
View at: Publisher Site | Google Scholar
Z. Varghese, J. F. Moorhead, and X. Z. Ruan, “The PPARα ligand fenofibrate: meeting multiple targets in diabetic nephropathy,” Kidney International, vol. 69, no. 9, pp. 1490–1491, 2006.
View at: Publisher Site | Google Scholar
C. W. Park, Y. Zhang, X. Zhang et al., “PPARα agonist fenofibrate improves diabetic nephropathy in db/db mic,” Kidney International, vol. 69, no. 9, pp. 1511–1517, 2006.
View at: Publisher Site | Google Scholar
I. Shirinsky, O. Polovnikova, N. Kalinovskaya, and V. Shirinsky, “The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study,” Rheumatology International, vol. 33, no. 12, pp. 3045–3048, 2013.
View at: Google Scholar
H. M. Ollila, S. Utge, E. Kronholm et al., “TRIB1 constitutes a molecular link between regulation of sleep and lipid metabolism in humans,” Translational Psychiatry, vol. 2, article e97, 2012.
View at: Publisher Site | Google Scholar
E. A. Lucassen, K. I. Rother, and G. Cizza, “Interacting epidemics? Sleep curtailment, insulin resistance, and obesity,” Annals of the New York Academy of Sciences, vol. 1264, no. 1, pp. 110–134, 2012.
View at: Google Scholar
Y. Zhang, J. L. Davis, and W. Li, “Identification of tribbles homolog 2 as an autoantigen in autoimmune uveitis by phage display,” Molecular Immunology, vol. 42, no. 11, pp. 1275–1281, 2005.
View at: Publisher Site | Google Scholar
V. Cvetkovic-Lopes, L. Bayer, S. Dorsaz et al., “Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients,” Journal of Clinical Investigation, vol. 120, no. 3, pp. 713–719, 2010.
View at: Publisher Site | Google Scholar
M. Kawashima, L. Lin, S. Tanaka et al., “Anti-tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy,” Sleep, vol. 33, no. 7, pp. 869–874, 2010.
View at: Google Scholar
H. Toyoda, S. Tanaka, T. Miyagawa, Y. Honda, K. Tokunaga, and M. Honda, “Anti-tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy,” Sleep, vol. 33, no. 7, pp. 875–878, 2010.
View at: Google Scholar
A. Katzav, M. T. Arango, S. Kivity et al., “Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice,” Journal of Autoimmunity, vol. 45, pp. 24–30, 2013.
View at: Google Scholar
S.-C. Wei, I. M. Rosenberg, Z. Cao, A. S. Huett, R. J. Xavier, and D. K. Podolsky, “Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling,” Inflammatory Bowel Diseases, vol. 18, no. 5, pp. 877–888, 2012.
View at: Publisher Site | Google Scholar
Y. Kozutsumi, M. Segal, K. Normington, M.-J. Gething, and J. Sambrook, “The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins,” Nature, vol. 332, no. 6163, pp. 462–464, 1988.
View at: Google Scholar
J. S. Cox, C. E. Shamu, and P. Walter, “Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase,” Cell, vol. 73, no. 6, pp. 1197–1206, 1993.
View at: Publisher Site | Google Scholar
J. S. Cox, R. E. Chapman, and P. Walter, “The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane,” Molecular Biology of the Cell, vol. 8, no. 9, pp. 1805–1814, 1997.
View at: Google Scholar
M. Matsumoto, M. Minami, K. Takeda, Y. Sakao, and S. Akira, “Ectopic expression of CHOP (GADD153) induces apoptosis in M1 myeloblastic leukemia cells,” FEBS Letters, vol. 395, no. 2-3, pp. 143–147, 1996.
View at: Publisher Site | Google Scholar
H. Zinszner, M. Kuroda, X. Wang et al., “CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum,” Genes and Development, vol. 12, no. 7, pp. 982–995, 1998.
View at: Google Scholar
C. Xu, B. Bailly-Maitre, and J. C. Reed, “Endoplasmic reticulum stress: cell life and death decisions,” Journal of Clinical Investigation, vol. 115, no. 10, pp. 2656–2664, 2005.
View at: Publisher Site | Google Scholar
R. Cunard and K. Sharma, “The endoplasmic reticulum stress response and diabetic kidney disease,” The American Journal of Physiology, vol. 300, no. 5, pp. 1054–1061, 2011.
View at: Publisher Site | Google Scholar
K. Kimura, H. Jin, M. Ogawa, and T. Aoe, “Dysfunction of the ER chaperone BiP accelerates the renal tubular injury,” Biochemical and Biophysical Research Communications, vol. 366, no. 4, pp. 1048–1053, 2008.
View at: Publisher Site | Google Scholar
V. Esposito, F. Grosjean, J. Tan et al., “CHOP deficiency results in elevated lipopolysaccharide-induced inflammation and kidney injury,” The American Journal of Physiology, vol. 304, no. 4, pp. F440–F450, 2013.
View at: Google Scholar
M. Peyrou, P. E. Hanna, and A. E. Cribb, “Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys,” Toxicological Sciences, vol. 99, no. 1, pp. 346–353, 2007.
View at: Publisher Site | Google Scholar
D. Kong, L. Zhuo, C. Gao et al., “Erythropoietin protects against cisplatin-induced nephrotoxicity by attenuating endoplasmic reticulum stress-induced apoptosis,” Journal of Nephrology, vol. 26, no. 1, pp. 219–227, 2013.
View at: Google Scholar
X. Gao, L. Fu, M. Xiao et al., “The nephroprotective effect of tauroursodeoxycholic acid on ischaemia/reperfusion-induced acute kidney injury by inhibiting endoplasmic reticulum stress,” Basic and Clinical Pharmacology and Toxicology, vol. 111, no. 1, pp. 4–23, 2012.
View at: Publisher Site | Google Scholar
Y. Bando, Y. Tsukamoto, T. Katayama et al., “ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death,” The FASEB Journal, vol. 18, no. 12, pp. 1401–1403, 2004.
View at: Publisher Site | Google Scholar
Z.-F. Luo, B. Feng, J. Mu et al., “Effects of 4-phenylbutyric acid on the process and development of diabetic nephropathy induced in rats by streptozotocin: regulation of endoplasmic reticulum stress-oxidative activation,” Toxicology and Applied Pharmacology, vol. 246, no. 1-2, pp. 49–57, 2010.
View at: Publisher Site | Google Scholar
A. V. Cybulsky, T. Takano, J. Papillon, and K. Bijian, “Role of the endoplasmic reticulum unfolded protein response in glomerular epithelial cell injury,” Journal of Biological Chemistry, vol. 280, no. 26, pp. 24396–24403, 2005.
View at: Publisher Site | Google Scholar
E. J. Brown, M. W. Albers, T. B. S. Tae Bum Shin et al., “A mammalian protein targeted by G1-arresting rapamycin-receptor complex,” Nature, vol. 369, no. 6483, pp. 756–758, 1994.
View at: Publisher Site | Google Scholar
M. I. Chiu, H. Katz, and V. Berlin, “RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 26, pp. 12574–12578, 1994.
View at: Publisher Site | Google Scholar
D. M. Sabatini, H. Erdjument-Bromage, M. Lui, P. Tempst, and S. H. Snyder, “RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs,” Cell, vol. 78, no. 1, pp. 35–43, 1994.
View at: Publisher Site | Google Scholar
W. Lieberthal and J. S. Levine, “Mammalian target of rapamycin and the kidney. II: pathophysiology and therapeutic implications,” The American Journal of Physiology, vol. 303, no. 2, pp. F180–F191, 2012.
View at: Google Scholar
D. P. Cinà, T. Onay, A. Paltoo et al., “Inhibition of MTOR disrupts autophagic flux in podocytes,” Journal of the American Society of Nephrology, vol. 23, no. 3, pp. 412–420, 2012.
View at: Publisher Site | Google Scholar
M. Gödel, B. Hartleben, N. Herbach et al., “Role of mTOR in podocyte function and diabetic nephropathy in humans and mice,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2197–2209, 2011.
View at: Publisher Site | Google Scholar
N. Cybulski and M. N. Hall, “TOR complex 2: a signaling pathway of its own,” Trends in Biochemical Sciences, vol. 34, no. 12, pp. 620–627, 2009.
View at: Publisher Site | Google Scholar
E. Jacinto, R. Loewith, A. Schmidt et al., “Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive,” Nature Cell Biology, vol. 6, no. 11, pp. 1122–1128, 2004.
View at: Publisher Site | Google Scholar
V. A. Stevens, S. Saad, X.-M. Chen, and C. A. Pollock, “The interdependence of EGF-R and SGK-1 in fibronectin expression in primary kidney cortical fibroblast cells,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 5, pp. 1047–1054, 2007.
View at: Publisher Site | Google Scholar
M. Lu, J. Wang, K. T. Jones et al., “mTOR complex-2 activates ENaC by phosphorylating SGK1,” Journal of the American Society of Nephrology, vol. 21, no. 5, pp. 811–818, 2010.
View at: Publisher Site | Google Scholar
B. Vollenbröker, B. George, M. Wolfgart, M. A. Saleem, H. Pavenstädt, and T. Weide, “mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes,” The American Journal of Physiology, vol. 296, no. 2, pp. F418–F426, 2009.
View at: Publisher Site | Google Scholar
D. Mascarenhas, S. Routt, and B. K. Singh, “Mammalian target of rapamycin complex 2 regulates inflammatory response to stress,” Inflammation Research, vol. 61, no. 12, pp. 1395–1404, 2012.
View at: Google Scholar
W. Fan, K. Cheng, X. Qin et al., “mTORC1 and mTORC2 play different roles in the functional survival of transplanted adipose-derived stromal cells in hind limb ischemic mice via regulating inflammation in vivo,” Stem Cells, vol. 31, no. 1, pp. 203–214, 2013.
View at: Google Scholar
T. B. Huber, C. L. Edelstein, B. Hartleben et al., “Emerging role of autophagy in kidney function, diseases and aging,” Autophagy, vol. 8, no. 7, 2012.
View at: Google Scholar
Y. Tanaka, S. Kume, M. Kitada et al., “Autophagy as a therapeutic target in diabetic nephropathy,” Experimental Diabetes Research, vol. 2012, Article ID 628978, 2012.
View at: Publisher Site | Google Scholar
B. Hartleben, M. Gödel, C. Meyer-Schwesinger et al., “Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1084–1096, 2010.
View at: Publisher Site | Google Scholar
S. Miranda, Á. González-Rodríguez, M. García-Ramírez et al., “Beneficial effects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions,” Journal of Cellular Physiology, vol. 227, no. 6, pp. 2352–2362, 2012.
View at: Publisher Site | Google Scholar
C. Appenzeller-Herzog and M. N. Hall, “Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling,” Trends in Cell Biology, vol. 22, no. 5, pp. 274–282, 2012.
View at: Publisher Site | Google Scholar
W.-X. Ding, H.-M. Ni, W. Gao et al., “Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival,” Journal of Biological Chemistry, vol. 282, no. 7, pp. 4702–4710, 2007.
View at: Publisher Site | Google Scholar
M. Høyer-Hansen and M. Jäättelä, “Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium,” Cell Death and Differentiation, vol. 14, no. 9, pp. 1576–1582, 2007.
View at: Publisher Site | Google Scholar
M. Ogata, S.-I. Hino, A. Saito et al., “Autophagy is activated for cell survival after endoplasmic reticulum stress,” Molecular and Cellular Biology, vol. 26, no. 24, pp. 9220–9231, 2006.
View at: Publisher Site | Google Scholar
G. Velasco, T. Verfaillie, M. Salazar, and P. Agostinis, “Linking ER stress to autophagy: potential implications for cancer therapy,” International Journal of Cell Biology, vol. 2010, Article ID 930509, 19 pages, 2010.
View at: Publisher Site | Google Scholar
Y. Wei, S. Pattingre, S. Sinha, M. Bassik, and B. Levine, “JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy,” Molecular Cell, vol. 30, no. 6, pp. 678–688, 2008.
View at: Publisher Site | Google Scholar
Y. Kouroku, E. Fujita, I. Tanida et al., “ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation,” Cell Death and Differentiation, vol. 14, no. 2, pp. 230–239, 2007.
View at: Publisher Site | Google Scholar
E. Kiss-Toth, “Tribbles: “puzzling” regulators of cell signalling,” Biochemical Society Transactions, vol. 39, no. 2, pp. 684–687, 2011.
View at: Publisher Site | Google Scholar
L. E. White and H. T. Hassoun, “Inflammatory mechanisms of organ crosstalk during ischemic acute kidney injury,” International Journal of Nephrology, vol. 2012, Article ID 505197, 8 pages, 2012.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2013 Robyn Cunard. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3961

Downloads

1967

Citations