The development of the endocrine pancreas is under the control of highly orchestrated, cross-interacting transcription factors. Pancreas genesis is initiated by the emergence of a Pdx1/Ptf1a marked territory at the foregut/midgut junction. A small fraction of pancreatic fated cells activates the expression of the bHLH transcription factor Ngn3 triggering the endocrine cell program, thus giving rise to beta-, alpha-, delta-, PP-, and epsilon-cells, producing insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin, respectively. Two transcription factors, Pax4 and Arx, play a crucial role in differential endocrine cell subtype specification. They were shown to be necessary and sufficient to endow endocrine progenitors with either a beta- or alpha-cell destiny. Interestingly, whereas the forced expression of Arx in beta-cells converts these into cells exhibiting alpha- and PP-cell characteristics, the sole expression of Pax4 in alpha-cells promotes alpha-cell-neogenesis and the acquisition of beta-cell features, the resulting beta-like cells being capable of counteracting chemically induced diabetes. Gaining new insights into the molecular mechanisms controlling Pax4 and Arx expression in the endocrine pancreas may therefore pave new avenues for the therapy of diabetes.

Monica Courtney

Tamara Rabe

Patrick Collombat

Ahmed Mansouri

Pax4 and Arx Represent Crucial Regulators of the Development of the Endocrine Pancreas

Nuclear pore complexes (NPCs) are the sole gateways between the nucleus and the cytoplasm of eukaryotic cells and they mediate all macromolecular trafficking between these cellular compartments. Nucleocytoplasmic transport is highly selective and precisely regulated and as such an important aspect of normal cellular function. Defects in this process or in its machinery have been linked to various human diseases, including cancer. Nucleoporins, which are about 30 proteins that built up NPCs, are critical players in nucleocytoplasmic transport and have also been shown to be key players in numerous other cellular processes, such as cell cycle control and gene expression regulation. This review will focus on the three nucleoporins Nup98, Nup214, and Nup358. Common to them is their significance in nucleocytoplasmic transport, their multiple other functions, and being targets for chromosomal translocations that lead to haematopoietic malignancies, in particular acute myeloid leukaemia. The underlying molecular mechanisms of nucleoporin-associated leukaemias are only poorly understood but share some characteristics and are distinguished by their poor prognosis and therapy outcome.

Birthe Fahrenkrog

Nucleoporin Gene Fusions and Hematopoietic Malignancies

Multidrug resistance (MDR) in cancer cells is a phenotype whereby cells display reduced sensitivity to anticancer drugs, based on a variety of mechanisms, including an increase in drug efflux, the reduction of drug uptake, the activation of cell growth and survival signaling, the promotion of DNA repair, and the inhibition of apoptosis signaling. Increased expression of the plasma membrane drug efflux pumps, the ATP-binding cassette (ABC) transporters, is involved in MDR. P-Glycoprotein/ABCB1 is a member of the ABC transporter family, and facilitates the efflux of various anticancer drugs, including anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, and kinase inhibitors, from cells. P-Glycoprotein is also expressed in normal tissues and cells, including the kidney, liver, colon, and adrenal gland, to transport and/or secrete substrates and at the blood-brain, blood-placenta, and blood-testis barriers to protect these tissues from toxic substances. To understand the mechanistic functions of P-glycoprotein and to overcome MDR, investigators have identified the substrates and competitive inhibitors of P-glycoprotein. Recently, we and other groups reported associations between cellular signaling pathways and the expression, stability, degradation, localization, and activity of P-glycoprotein. The present review summarizes the currently available information about the transcriptional and posttranslational regulation of P-glycoprotein expression and function.

Kazuhiro Katayama

Kohji Noguchi

Yoshikazu Sugimoto

Regulations of P-Glycoprotein/ABCB1/MDR1 in Human Cancer Cells

Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression.

Jeong-Hun Kang

Protein Kinase C (PKC) Isozymes and Cancer

This review presents a general view of all types of melanin in all types of organisms. Melanin is frequently considered just an animal cutaneous pigment and is treated separately from similar fungal or bacterial pigments. Similarities concerning the phenol precursors and common patterns in the formation routes are discussed. All melanins are formed in a first enzymatically-controlled phase, generally a phenolase, and a second phase characterized by an uncontrolled polymerization of the oxidized intermediates. In that second phase, quinones derived from phenol oxidation play a crucial role. Concerning functions, all melanins show a common feature, a protective role, but they are not merely photoprotective pigments against UV sunlight. In pathogenic microorganisms, melanization becomes a virulence factor since melanin protects microbial cells from defense mechanisms in the infected host. In turn, some melanins are formed in tissues where sunlight radiation is not a potential threat. Then, their redox, metal chelating, or free radical scavenging properties are more important than light absorption capacity. These pigments sometimes behave as a double-edged sword, and inhibition of melanogenesis is desirable in different cells. Melanin biochemistry is an active field of research from dermatological, biomedical, cosmetical, and microbiological points of view, as well as fruit technology.

F. Solano

Melanins: Skin Pigments and Much More&#x2014;Types, Structural Models, Biological Functions, and Formation Routes

Cancer immunotherapy is a promising and effective treatment modality for patients with cancers. Cytokine, anticytokine, and antibody therapies appear to be effective in treating various forms of cancer. The human papillomavirus vaccine is protective for cervical cancer, and this discovery has paved the way to the development of cancer vaccines for other forms of virus-associated cancers such as liver cancer and Merkel cell carcinoma. Clinical trials have demonstrated that adoptive cell therapy using tumor-infiltrating lymphocytes can induce tumor regression in approximately 75&#x25; of metastatic melanoma patients, suggesting the possibility of using similar technique to effectively treat breast, lung, and renal cancers in the near future. Besides, genetically engineered T cells transduced with genes encoding specific T cell receptors and chimeric antigen receptors have been shown effective in the treatment of cancer patients. These studies suggest that combination therapies are superior choices in cancer immunotherapy for patients.

Juhua Zhou

Advances and Prospects in Cancer Immunotherapy

Programmed cell death has been studied for decades in mammalian cells, but simpler organisms, including prokaryotes, plants, and fungi, also undergo regulated forms of cell death. We highlight the usefulness of the filamentous fungus Neurospora crassa as a model organism for the study of programmed cell death. In N. crassa, cell death can be triggered genetically due to hyphal fusion between individuals with different allelic specificities at het loci, in a process called &#x201C;heterokaryon incompatibility.&#x201D; Chemical induction of cell death can also be achieved upon exposure to death-inducing agents like staurosporine, phytosphingosine, or hydrogen peroxide. A summary of the recent advances made by our and other groups on the discovery of the mechanisms and mediators underlying the process of cell death in N. crassa is presented.

A. Pedro Gon&#xe7;alves

Arnaldo Videira

Programmed Cell Death in Neurospora crassa

The MYC family of proteins is a group of basic-helix-loop-helix-leucine zipper transcription factors that feature prominently in cancer. Overexpression of MYC is observed in the vast majority of human malignancies and promotes an extraordinary set of changes that impact cell proliferation, growth, metabolism, DNA replication, cell cycle progression, cell adhesion, differentiation, and metastasis. The purpose of this review is to introduce the reader to the mammalian family of MYC proteins, highlight important functional properties that endow them with their potent oncogenic potential, describe their mechanisms of action and of deregulation in cancer cells, and discuss efforts to target the unique properties of MYC, and of MYC-driven tumors, to treat cancer.

William P. Tansey

Mammalian MYC Proteins and Cancer

We tell of a journey that led to discovery of amyloids formed by yeast cell adhesins and their importance in biofilms and host immunity. We begin with the identification of the adhesin functional amyloid-forming sequences that mediate fiber formation in vitro. Atomic force microscopy and confocal microscopy show 2-dimensional amyloid &#x201C;nanodomains&#x201D; on the surface of cells that are activated for adhesion. These nanodomains are arrays of adhesin molecules that bind multivalent ligands with high avidity. Nanodomains form when adhesin molecules are stretched in the AFM or under laminar flow. Treatment with anti-amyloid perturbants or mutation of the amyloid sequence prevents adhesion nanodomain formation and activation. We are now discovering biological consequences. Adhesin nanodomains promote formation and maintenance of biofilms, which are microbial communities. Also, in abscesses within candidiasis patients, we find adhesin amyloids on the surface of the fungi. In both human infection and a Caenorhabditis elegans infection model, the presence of fungal surface amyloids elicits anti-inflammatory responses. Thus, this is a story of how fungal adhesins respond to extension forces through formation of cell surface amyloid nanodomains, with key consequences for biofilm formation and host responses.

Peter N. Lipke

Caleen Ramsook

Melissa C. Garcia-Sherman

Desmond N. Jackson

Cho X. J. Chan

Michael Bois

Stephen A. Klotz

Between Amyloids and Aggregation Lies a Connection with Strength and Adhesion

Ion channels are essential for basic cellular function and for processes including sensory perception and intercellular communication in multicellular organisms. Voltage-gated potassium (Kv) channels facilitate dynamic cellular repolarization during an action potential, opening in response to membrane depolarization to facilitate K+ efflux. In both excitable and nonexcitable cells other, constitutively active, K+ channels provide a relatively constant repolarizing force to control membrane potential, ion homeostasis, and secretory processes. Of the forty known human Kv channel pore-forming &#x3B1; subunits that coassemble in various combinations to form the fundamental tetrameric channel pore and voltage sensor module, KCNQ1 is unique. KCNQ1 stands alone in having the capacity to form either channels that are voltage-dependent and require membrane depolarization for activation, or constitutively active channels. In mammals, KCNQ1 regulates processes including gastric acid secretion, thyroid hormone biosynthesis, salt and glucose homeostasis, and cell volume and in some species is required for rhythmic beating of the heart. In this review, the author discusses the unique functional properties, regulation, cell biology, diverse physiological roles, and involvement in human disease states of this chameleonic K+ channel.

Geoffrey W. Abbott

Biology of the KCNQ1 Potassium Channel

Vacuolar H+-ATPases (V-ATPases) are large multisubunit proton pumps that are required for housekeeping acidification of membrane-bound compartments in eukaryotic cells. Mammalian V-ATPases are composed of 13 different subunits. Their housekeeping functions include acidifying endosomes, lysosomes, phagosomes, compartments for uncoupling receptors and ligands, autophagosomes, and elements of the Golgi apparatus. Specialized cells, including osteoclasts, intercalated cells in the kidney and pancreatic beta cells, contain both the housekeeping V-ATPases and an additional subset of V-ATPases, which plays a cell type specific role. The specialized V-ATPases are typically marked by the inclusion of cell type specific isoforms of one or more of the subunits. Three human diseases caused by mutations of isoforms of subunits have been identified. Cancer cells utilize V-ATPases in unusual ways; characterization of V-ATPases may lead to new therapeutic modalities for the treatment of cancer. Two accessory proteins to the V-ATPase have been identified that regulate the proton pump. One is the (pro)renin receptor and data is emerging that indicates that V-ATPase may be intimately linked to renin/angiotensin signaling both systemically and locally. In summary, V-ATPases play vital housekeeping roles in eukaryotic cells. Specialized versions of the pump are required by specific organ systems and are involved in diseases.

L. Shannon Holliday

Vacuolar H+-ATPase: An Essential Multitasking Enzyme in Physiology and Pathophysiology

Since the beginning of the 20th century, scientists have tried to stimulate the antitumour activities of the immune system to fight against cancer. However, the scientific effort devoted on the development of cancer immunotherapy has not been translated into the expected clinical success. On the contrary, classical antineoplastic treatments such as surgery, radiotherapy, and chemotherapy are the first line of treatment. Nevertheless, there is compelling evidence on the immunogenicity of cancer cells and the capacity of the immune system to expand cancer-specific effector cytotoxic T cells. However, the effective activation of anticancer T cell responses strongly depends on efficient tumour antigen presentation from professional antigen presenting cells such as dendritic cells (DCs). Several strategies have been used to boost DC antigen presenting functions, but at the end cancer immunotherapy is not as effective as would be expected according to preclinical models. In this review, we comment on these discrepancies, focusing our attention on the contribution of regulatory T cells and myeloid-derived suppressor cells to the lack of therapeutic success of DC-based cancer immunotherapy.

David Escors

Tumour Immunogenicity, Antigen Presentation, and Immunological Barriers in Cancer Immunotherapy

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