Research Article | Open Access
Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor- (PPAR)
The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor- (PPAR) was examined. PPAR-binding protein (PBP), PPAR coactivator-1 (PGC-1), steroid receptor coactivator-1 (SRC-1), and CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) affected PPAR activity in the presence of Wy-14,643. The effects on PPAR activity in light of increased or decreased expression of these coactivators were qualitatively different depending on the ligand examined. Diminished expression of PGC-1, SRC-1, or PBP by RNAi plasmids affected natural or synthetic agonist activity whereas only Wy-14,643 was affected by decreased PGC-1. The interaction of PPAR with an LXXLL-containing peptide library showed ligand-specific patterns, indicative of differences in conformational change. The association of coactivators to PPAR occurs predominantly via the carboxyl-terminus and mutating LHPLL to LHPAA resulted in a dominant-negative construct. This research confirms that coactivator recruitment to PPAR is ligand-dependent and that selective receptor modulators (SRMs) of this important protein are likely.
- C Dreyer, G Krey, H Keller, F Givel, G Helftenbein, and W Wahli, “Control of the peroxisomal -oxidation pathway by a novel family of nuclear hormone receptors,” Cell, vol. 68, no. 5, pp. 879–887, 1992.
- R A Roberts, N H James, N J Woodyatt, N Macdonald, and J D Tugwood, “Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPAR),” Carcinogenesis, vol. 19, no. 1, pp. 43–48, 1998.
- N H James, J H Gill, R Brindle et al., “Peroxisome proliferator-activated receptor (PPAR) alpha-regulated growth responses and their importance to hepatocarcinogenesis,” Toxicology Letters, vol. 102-103, pp. 91–96, 1998.
- M J Olson, “DNA strand breaks induced by hydrogen peroxide in isolated rat hepatocytes,” Journal of Toxicology and Environmental Health, vol. 23, no. 3, pp. 407–423, 1988.
- J K Reddy and M S Rao, “Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesis,” Mutation Research, vol. 214, no. 1, pp. 63–68, 1989.
- Y Yu, P H Correll, and J P Vanden Heuvel, “Conjugated linoleic acid decreases production of pro-inflammatory products in macrophages: evidence for a PPAR-dependent mechanism,” Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, vol. 1581, no. 3, pp. 89–99, 2002.
- V H Coulthard, S Matsuda, and D M Heery, “An extended LXXLL motif sequence determines the nuclear receptor binding specificity of TRAP220,” Journal of Biological Chemistry, vol. 278, no. 13, pp. 10942–10951, 2003.
- D M Heery, S Hoare, S Hussain, M G Parker, and H Sheppard, “Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors,” Journal of Biological Chemistry, vol. 276, no. 9, pp. 6695–6702, 2001.
- R B Lanz, N J McKenna, S A Onate et al., “A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex,” Cell, vol. 97, no. 1, pp. 17–27, 1999.
- J Bragança, T Swingler, F IR Marques et al., “Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2,” Journal of Biological Chemistry, vol. 277, no. 10, pp. 8559–8565, 2002.
- R T Nolte, G B Wisely, S Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator- activated receptor-,” Nature, vol. 395, no. 6698, pp. 137–143, 1998.
- J Uppenberg, C Svensson, M Jaki, G Bertilsson, L Jendeberg, and A Berkenstam, “Crystal structure of the ligand binding domain of the human nuclear receptor PPAR,” Journal of Biological Chemistry, vol. 273, no. 47, pp. 31108–31112, 1998.
- J K Reddy, “Carcinogenicity of peroxisome proliferators: evaluation and mechanisms,” Biochemical Society Transactions, vol. 18, no. 1, pp. 92–94, 1990.
- C E Connor, J D Norris, G Broadwater et al., “Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor,” Cancer Research, vol. 61, no. 7, pp. 2917–2922, 2001.
- P Dowell, V J Peterson, T M Zabriskie, and M Leid, “Ligand-induced peroxisome proliferator-activated receptor conformational change,” Journal of Biological Chemistry, vol. 272, no. 3, pp. 2013–2020, 1997.
- W K Sumanasekera, E S Tien, J W Davis, II, R Turpey, G H Perdew, and J P Vanden Heuvel, “Heat shock protein-90 (Hsp90) acts as a repressor of peroxisome proliferator-activated receptor- (PPAR) and PPAR activity,” Biochemistry, vol. 42, no. 36, pp. 10726–10735, 2003.
- J D Tugwood, P R Holden, N H James, R A Prince, and R A Roberts, “A peroxisome proliferator-activated receptor-alpha (PPAR) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPAR: implications for species differences in responses to peroxisome proliferators,” Archives of Toxicology, vol. 72, no. 3, pp. 169–177, 1998.
- C-Y Chang, J D Norris, H Grøn et al., “Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors and ,” Molecular and Cellular Biology, vol. 19, no. 12, pp. 8226–8239, 1999.
- E S Tien, J W Davis, and J P Vanden Heuvel, “Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor coregulator,” Journal of Biological Chemistry, vol. 279, no. 23, pp. 24053–24063, 2004.
- Y Kodera, K-I Takeyama, A Murayama, M Suzawa, Y Masuhiro, and S Kato, “Ligand type-specific interactions of peroxisome proliferator-activated receptor with transcriptional coactivators,” Journal of Biological Chemistry, vol. 275, no. 43, pp. 33201–33204, 2000.
- J Xu, Y Qiu, F J DeMayo, S Y Tsai, M-J Tsai, and B W O'Malley, “Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene,” Science, vol. 279, no. 5358, pp. 1922–1925, 1998.
- J D Graham, D L Bain, J K Richer, T A Jackson, L Tung, and K B Horwitz, “Nuclear receptor conformation, coregulators, and tamoxifen-resistant breast cancer,” Steroids, vol. 65, no. 10-11, pp. 579–584, 2000.
- M Xu, K J Modarress, J EW Meeker, and S S Jr Simons, “Steroid-induced conformational changes of rat glucocorticoid receptor cause altered trypsin cleavage of the putative helix 6 in the ligand binding domain,” Molecular and Cellular Endocrinology, vol. 155, no. 1-2, pp. 85–100, 1999.
- R K Sharma, B G Lake, R Makowski et al., “Differential induction of peroxisomal and microsomal fatty-acid-oxidising enzymes by peroxisome proliferators in rat liver and kidney. Characterisation of a renal cytochrome P-450 and implications for peroxisome proliferation,” European Journal of Biochemistry, vol. 184, no. 1, pp. 69–78, 1989.
- S Haubenwallner, A D Essenburg, B C Barnett et al., “Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action,” Journal of Lipid Research, vol. 36, no. 12, pp. 2541–2551, 1995.
- T Takahashi, T Hirano, K Okada, and M Adachi, “Clinical and Experimental: apolipoprotein CIII deficiency prevents the development of hypertriglyceridemia in streptozotocin-induced diabetic mice,” Metabolism, vol. 52, no. 10, pp. 1354–1359, 2003.
- C Karagianni, S Stabouli, K Roumeliotou et al., “Severe hypertriglyceridaemia in diabetic ketoacidosis: clinical and genetic study,” Diabetic Medicine, vol. 21, no. 4, pp. 380–382, 2004.
- H Miyamoto, M Rahman, H Takatera et al., “A dominant-negative mutant of androgen receptor coregulator ARA54 inhibits androgen receptor-mediated prostate cancer growth,” Journal of Biological Chemistry, vol. 277, no. 7, pp. 4609–4617, 2002.
- Y Wang and R J Miksicek, “Identification of a dominant negative form of the human estrogen receptor,” Molecular Endocrinology, vol. 5, no. 11, pp. 1707–1715, 1991.
- J J Palvimo, P J Kallio, T Ikonen, M Mehto, and O A Janne, “Dominant negative regulation of trans-activation by the rat androgen receptor: roles of the N-terminal domain and heterodimer formation,” Molecular Endocrinology, vol. 7, no. 11, pp. 1399–1407, 1993.
- W Seol, H-S Choi, and D D Moore, “An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors,” Science, vol. 272, no. 5266, pp. 1336–1339, 1996.
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