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Gene regulation by nuclear hormone receptors. Molecular genetics of acute promyelocytic leukemiaThe overall goals of our research program are (1) to understand the molecular mechanisms of gene regulation by steroid/nuclear hormone receptors. (2) to identify and clone new genes involved in regulating nuclear receptor function. and (3) to develop molecular tools to combat hormone related human diseases including acute promyelocytic leukemia. breast cancer and diabetes. Nuclear receptors are ligand dependent transcription factors that regulate genes critical to such biological processes as development. reproduction. and homeostasis. These receptors can function as molecular switches. alternating between states of repression and activation depending on the availability of cognate hormone. Our lab has cloned the first nuclear receptor corepressor SMRT that associates with the unliganded retinoid and thyroid hormone receptors to mediate transcriptional repression of target genes. SMRT and the related corepressor N-CoR are known to recruit histone deacetylase complex to modify chromatin structure for transcriptional repression. Our lab has also cloned the important nuclear receptor coactivator RAC3. also known as AIB1 for it is amplified in breast cancer. The RAC3 coactivator interacts with ligand-bound receptors. and then serves as a bridging factor to recruit additional coactivators such as CBP/p300 and P/CAF for acetylating histones and transcriptional activation. Finally. we have also cloned the pro-apoptotic protein Daxx based on interaction with the promyelocytic leukemic protein PML. which fuses with the retinoid acid receptor in t(15;17) translocation. Overall. we are interested in elucidating the molecular mechanisms that the PML-RAR oncoprotein uses to induce acute promyelocytic leukemia. Our lab is well equipped and highly committed to continue to identify new mechanisms and to clone new genes involved in hormone action. We have the state-of-art equipment and we utilize the latest technology in our daily research. We hope that one day our research will lead to development of new molecular tools or strategies to help combat hormone related human diseases. Selected PublicationsChisamore MJ, Cunningham ME, Flores O, Wilkinson HA, Chen JD. (2009) Characterization of a novel small molecule subtype specific estrogen-related receptor alpha antagonist in MCF-7 breast cancer cells. PLoS ONE. 4(5):e5624. Chisamore MJ, Wilkinson HA, Flores O, Chen JD. (2009) Estrogen-related receptor-alpha antagonist inhibits both estrogen receptor-positive and estrogen receptor-negative breast tumor growth in mouse xenografts. Mol Cancer Ther. 8(3):672-81. Lin YS, Yasuda K, Assem M, Cline C, Barber J, Li CW, Kholodovych V, Ai N, Chen JD, Welsh WJ, Ekins S, Schuetz EG. (2009) The major human pregnane X receptor (PXR) splice variant, PXR.2, exhibits significantly diminished ligand-activated transcriptional regulation. Drug Metab Dispos. 37(6):1295-304. Li CW, Dinh GK, Chen JD. (2009) Preferential physical and functional interaction of pregnane X receptor with the SMRTalpha isoform. Mol Pharmacol. 75(2):363-73. Neilsen PM, Cheney KM, Li CW, Chen JD, Cawrse JE, Schulz RB, Powell JA, Kumar R, Callen DF. (2008) Identification of ANKRD11 as a p53 coactivator. J Cell Sci. 121(Pt 21):3541-52. Li CW, Dinh GK, Zhang A, Chen JD. (2008) Ankyrin repeats cofactors interact with ADA3 and modulate its coactivator function. Biochem J. 413(2):349-57. Yeung PL, Chen LY, Tsai SC, Zhang A, Chen JD. (2008) Daxx contains two nuclear localization signals and interacts with importin alpha3. J Cell Biochem. 103(2):456-70. Zhang A, Li CW, Tsai SC, Chen JD. (2007) Subcellular localization of ankyrin repeats cofactor-1 regulates its corepressor activity. J Cell Biochem. 358(4):1034-40. Yeung PL, Zhang A, Chen JD. (2006) Nuclear localization of coactivator RAC3 is mediated by a bipartite NLS and importin alpha3. Biochem Biophys Res Commun. 348(1):13-24. Lin W, Shen G, Yuan X, Jain MR, Yu S, Zhang A, Chen JD, Kong AN. (2006) Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co-regulators. J Biochem Mol Biol. 39(3):304-10. Wang CY, Li CW, Chen JD, Welsh WJ. (2006) Structural model reveals key interactions in the assembly of the pregnane X receptor/corepressor complex. Mol Pharmacol. 69(5):1513-7. Johnson DR, Li CW, Chen LY, Ghosh JC, Chen JD. (2006) Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT). Mol Pharmacol. 69(1):99-108. Zhang A, Yeung PL, Li CW, Tsai SC, Dinh GK, Wu X, Li H, Chen JD. (2004) Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators. Johnson DR, Lovett JM, Hirsch M, Xia F, Chen JD. (2004) NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation. Biochem Biophys Res Commun. 318(3):714-8. Svensson MJ, Chen JD, Pirrotta V, Larsson J. (2003) The ThioredoxinT and deadhead gene pair encode testis- and ovary-specific thioredoxins in Drosophila melanogaster. Chen. L-Y. and Chen. J.D. (2003) Daxx silencing sensitizes cells to multiple apoptotic pathways. Mol. Cell. Biology 23: 7108-7121. Liu. J.. Li. H.. Burstein. S.H.. Zurier. R.B. and Chen. J.D. (2003) Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic Cannabinoid Ajulemic Acid. Mol Pharmacol 63: 1-10. Liao. G.. Chen. L-Y.. Zhang. A.. Godavarthy. A.. Xia. F.. Ghosh. J. C.. Li. H. and Chen. J.D.(2003) Regulation of androgen receptor activity by nuclear receptor Corepressor SMRT. J. Biol. Chem. 278: 5052-5061. Liu. Z.. Auboeuf. D.. Wong. J.. Chen. J.D.. Tsai. S.Y.. Tsai. M.-J.. and O'Malley. B.W. (2002) Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc. Natl. Acad. Sci. USA 99:7940-7944. Ghosh. J.. Yang. X.. Zhang. A.. Lambert. M.H.. Li. H.. Xu. H.E.. and Chen. J.D. (2002) Interactions that determine the assembly of a retinoid-X receptor/corepressor complex. Proc. Natl. Acad. Sci. USA 99:5842-5847. |
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