The classical estrogen receptor, ER?, is a ligand-regulated transcription factor important for normal development, homeostasis and reproduction, and consequently, understanding normal and pharmacological regulation of this receptor's activity is of major significance to human health. It is well accepted that the ability of ER? to regulate gene expression is dependent upon the transcriptional coregulators that ligand-bound receptors recruit to their target genes. The silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) coregulator was initially characterized as a corepressor for ER? bound to the selective estrogen receptor modulator (SERM), 4-hydroxytamoxifen (4HT), however, it can stimulate the activity of ER? bound to estradiol (E2) and this established SMRT as a dual coactivator/corepressor for ER?. Recent work demonstrates that the nature of SMRT interactions with ER? depend upon whether the receptor is bound to agonist or antagonist. Moreover, in addition to the well described activation of histone deacetylase 3 (HDAC3) by SMRT, this coregulator can also bind to a histone demethylase that promotes the transcriptional activity of ER?. The overall goal of the proposed work is to define the ability of two SMRT interacting proteins, with activating and repressive activities, respectively, to regulate ER?-dependent gene expression. The planned experiments will use state-of-the-art biological, cistromic and transcriptomic analysis to test whether differences in the nature of SMRT-ER? interactions contributes to the ability of these distinct complexes to bind and/or regulate ER? in a ligand- and gene-dependent manner, and whether the composition or activity of the repressive complexes can be regulated by cellular pathways. Using novel 3-dimensional culture of mammary epithelial cells that maintain steroid responsiveness and mouse models that enable the precise evaluation of the HDAC3 activation activity of SMRT in vivo, the ability of SMRT to regulate ER? transcriptional activity as well as mammary gland development will define the biological importance of SMRT for regulation of ER? responses to both agonists and antagonists in a physiological setting. Together, these planned studies will evaluate the hypothesis that differences in the proteins that SMRT recruits to ER? target genes are critical determinants of the effect of this coregulator on ER?-dependent gene expression. In so doing, the proposed work will provide critical insight into mechanisms of action of SMRT independent of HDAC3, and the contribution of SMRT to ER? regulation in estrogen-dependent disease such as breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053002-15
Application #
8759541
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
1997-09-22
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-04-30
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
Blackmore, Julia K; Karmakar, Sudipan; Gu, Guowei et al. (2014) The SMRT coregulator enhances growth of estrogen receptor-α-positive breast cancer cells by promotion of cell cycle progression and inhibition of apoptosis. Endocrinology 155:3251-61
Adikesavan, Anbu Karani; Karmakar, Sudipan; Pardo, Patricia et al. (2014) Activation of p53 transcriptional activity by SMRT: a histone deacetylase 3-independent function of a transcriptional corepressor. Mol Cell Biol 34:1246-61
Liu, Shuang; Han, Sang Jun; Smith, Carolyn L (2013) Cooperative activation of gene expression by agonists and antagonists mediated by estrogen receptor heteroligand dimer complexes. Mol Pharmacol 83:1066-77
Jiang, Xiang-Rong; Wang, Pan; Smith, Carolyn L et al. (2013) Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity. J Med Chem 56:2779-90
Smith, Carolyn L; Migliaccio, Ilenia; Chaubal, Vaishali et al. (2012) Elevated nuclear expression of the SMRT corepressor in breast cancer is associated with earlier tumor recurrence. Breast Cancer Res Treat 136:253-65
Hoffman, Kristi L; Foster, Estrella A; Smith, Carolyn L (2012) The terminal substituents of 7ýý, 6-hexanyl derivatives of estradiol determine their selective estrogen receptor modulator versus agonist activities. Steroids 77:496-503
Karmakar, Sudipan; Foster, Estrella A; Blackmore, Julia K et al. (2011) Distinctive functions of p160 steroid receptor coactivators in proliferation of an estrogen-independent, tamoxifen-resistant breast cancer cell line. Endocr Relat Cancer 18:113-27
Bruning, John B; Parent, Alexander A; Gil, German et al. (2010) Coupling of receptor conformation and ligand orientation determine graded activity. Nat Chem Biol 6:837-43
Karmakar, Sudipan; Gao, Tong; Pace, Margaret C et al. (2010) Cooperative activation of cyclin D1 and progesterone receptor gene expression by the SRC-3 coactivator and SMRT corepressor. Mol Endocrinol 24:1187-202
Karmakar, Sudipan; Foster, Estrella A; Smith, Carolyn L (2009) Estradiol downregulation of the tumor suppressor gene BTG2 requires estrogen receptor-alpha and the REA corepressor. Int J Cancer 124:1841-51

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