Privalsky, Martin L. - University of California, Davis

研究领域

Our research focuses on understanding how cells regulate their proliferation and differentiation and the aberrant events which lead to neoplasia. Our specific goal is a better understanding of the actions of the nuclear receptors (also known as nuclear hormone receptors) in normal cells and in disease. Nuclear receptors are a family of hormone-regulated transcription factors, and include the steroid, retinoid, and thyroid hormone receptors; collectively they play critical roles in vertebrate homeostasis, differentiation, and reproduction. Nuclear receptors bind to specific target genes and modulate gene expression in response to hormones of extracellular origin, Intriguingly, these receptors can either repress or activate transcription by recruiting partner proteins denoted corepressors and coactivators. An alpha-helical domain (helix 12) at the C-terminus of these receptors functions as a hormone-regulated “molecular toggle switch;” by altering its conformation, helix 12 determines whether a corepressor or a coactivator is recruited to the nuclear receptor. Notably, defects in the operation of the helix 12 toggle switch result in aberrant corepressor and coactivator acquisition and, as a result, human disease (including both endocrine and neoplastic disorders). Our research seeks to employ these aberrant receptors as tools to determine the molecular pathways that operate in human diseases and to elucidate the actions of the normal receptors in the normal cell. We are currently investigating the contributions of nuclear receptor function in normal adipose cell differentiation, in thyroid hormone resistance, in leukemia, and in renal clear cell and hepatocellular carcinomas.

近期论文

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Jimenez R, Privalsky ML. 2016. A Resistance to Thyroid Hormone Syndrome mutant operates through the target gene repertoire of the wild-type thyroid hormone receptor. Molecular and Cellular Endocrinology. In press. Privalsky ML, Snyder CA, Goodson ML. 2016. Corepressor diversification by alternative mRNA splicing is species specific. BMC Evolutionary Biology 16, 221-234. Snyder CA, Goodson ML, Schroeder AC, Privalsky ML. 2015. Regulation of corepressor alternative mRNA splicing by hormonal and metabolic signaling. Molecular and Cellular Endocrinology 413, 228-235. Goodson ML, Young BM, Snyder CA, Schroeder AC, Privalsky ML. 2014. Alteration of NCoR corepressor splicing in mice causes increased body weight and hepatosteatosis without glucose intolerance. Molecular and Cellular Biology 34, 4104-4114. Schroeder A, Jimenez R, Young BM, Privalsky ML. 2014. The ability of thyroid hormone receptors to sense T4 as an agonist depends on receptor isoform and on cellular cofactors. Molecular Endocrinology 28, 745-757. Schroeder AC, Privalsky ML. 2014. Thyroid hormones, T3 and T4, in the brain. Frontiers of Endocrinology (Lausanne). 5, 40-46. Hahm JB, Schroeder AC, Privalsky ML. 2014. The two major isoforms of thyroid hormone receptor, TR-alpha 1and TR-beta 1, preferentially partner with distinct panels of auxiliary proteins. Molecular and Cellular Endocrinology 383, 80-95. Zota AR, Linderholm L, Park JS, PetreasM, Guo T, Privalsky ML, Zoeller RT, Woodruff TJ, 2013. A temporal comparison of PBDEs, OH-PBDEs, PCBs, and OH-PCBs in the serum of second trimester pregnant women recruited from San Francisco General Hospital, California. Environmental Science and Technology. 48, 2512-2513. Hahm JB, Privalsky ML. 2013. Research Resource: Identification of novel coregulators specific for thyroid hormone receptor-beta 2. Molecular Endocrinology, 27, 840-859. Sinha RA. You SH, Zhou J, Siddique MM, Bay BH, Zhu X, Privalsky ML, Cheng SY, Stevens RD, Summers SA, Newgard CB, Lazar MA, Yen PM. 2012. Thyroid hormone stimulates lipid catabolism via activation of autophagy. Journal of Clinical Investigation 122, 2428-2438. Mengeling BJ, Goodson ML, Bourguet W, Privalsky ML. 2012. SMRTelpsilon, a corepressor variant that interacts with a unique subset of nuclear receptors and displays a high specificity for retinoic acid receptors. Molecular and Cellular Endocrinology 351, 306-316. Goodson ML, Mengeling BJ, Jonas BA, Privalsky ML. 2011. Alternative mRNA splicing of corepressors generates variants that play opposing roles in adipocyte differentiation. Journal of Biological Chemistry 286, 44988-44999. Lee SH, Young BM, Wei W, Chan IH, Privalsky ML. 2011. A mechanism for Pituitary-Resistance to Thyroid Hormone (PRTH) Syndrome: a loss in cooperative coactivator contacts by thyroid hormone receptor (TR)β2. Molecular Endocrinology 25, 1111-1125. Rosen MD, Chan IH, Privalsky ML. Mutant thyroid hormone receptors (TRs) isolated from distinct cancer types display distinct target gene specificities: a unique regulatory repertoire associated with renal clear cell carcinomas. Molecular Endocrinology 23, 1183-1192. Rosen MD, Privalsky ML, 2011. Thyroid hormone receptor mutations in cancer and resistance to thyroid hormone: perspective and prognosis. Journal of Thyroid Research Volume 2011 (2011), doi:10.4061/2011/361304 Varlakhanova N, Hahm J, Privalsky ML. 2011. Regulation of SMRT corepressor dimerization and composition by MAP kinase phosphorylation. Molecular and Cellular Endocrinology 332, 180-188. Mengeling BJ, Phan TQ, Goodson ML, Privalsky ML. 2011. Aberrant corepressor interactions implicated in PML-RARα and PLZF-RARα leukemogenesis reflect an altered recruitment and release of specific NCoR and SMRT splice variants. Journal of Biological Chemistry 286, 4236-4347 Varlakhanova N, Snyder C, Jose S, Hahm JB, Privalsky ML. 2010. Estrogen receptors recruit. SMRT and N-CoR corepressors through newly recognized contacts between the corepressor N-terminus and the receptor DNA binding domain. Molecular and Cellular Biology 30, 1434-1445. Phan TQ, Jow MM, Privalsky ML. 2010. DNA recognition by thyroid hormone and retinoic acid receptors: 3-4-5 rule modified. Molecular and Cellular Endocrinology 319, 88-98. Chan IH, Privalsky ML. 2010. A conserved lysine in the thyroid hormone receptor (TR)-alpha1 DNA binding domain, mutated in hepatocellular carcinoma, serves as a sensor for transcriptional regulation. Molecular Cancer Research 8,15-23. Chan IH, Privalsky ML. 2009. Thyroid hormone receptor (TR) mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire. Oncogene 28, 4162-4174. Chan IH, Privalsky ML. 2009, Isoform specific transcriptional activity of overlapping target genes that respond to thyroid hormone receptors alpha 1 and beta 1. Molecular Endocrinology 23, 1758-1775. Rosen MD, Privalsky ML. 2009. Thyroid hormone receptor mutations found in renal clear cell carcinomas alter corepressor release and reveal helix 12 as key determinant of corepressor specificity. Molecular Endocrinology 23, 1183-1192. Privalsky ML, Lee SH, Hahm JB, Young BM, Fong, RNG, Chan IH. 2009. The p160 coactivator PAS-B motif stabilized nuclear receptor binding and contributes to isoform-specific regulation by thyroid hormone receptors. Journal of Biological Chemistry 284, 19554-19563 Chen IH, Browosky, AD, Privalsky ML. 2008 A cautionary note as to the use of pBI-L and related luciferase vector in the study of thyroid endocrinology. Thyroid 18, 665-666.