Cooperative activation of cyclin D1 and progesterone receptor gene expression by the SRC-3 coactivator and SMRT corepressor.

Abstract

Although the ability of coactivators to enhance the expression of estrogen receptor-alpha (ERalpha) target genes is well established, the role of corepressors in regulating 17beta-estradiol (E2)-induced gene expression is poorly understood. Previous studies revealed that the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor is required for full ERalpha transcriptional activity in MCF-7 breast cancer cells, and we report herein the E2-dependent recruitment of SMRT to the regulatory regions of the progesterone receptor (PR) and cyclin D1 genes. Individual depletion of SMRT or steroid receptor coactivator (SRC)-3 modestly decreased E2-induced PR and cyclin D1 expression; however, simultaneous depletion revealed a cooperative effect of this coactivator and corepressor on the expression of these genes. SMRT and SRC-3 bind directly in an ERalpha-independent manner, and this interaction promotes E2-dependent SRC-3 binding to ERalpha measured by co-IP and SRC-3 recruitment to the cyclin D1 gene as measured by chromatin IP assays. Moreover, SMRT stimulates the intrinsic transcriptional activity of all of the SRC family (p160) coactivators. Our data link the SMRT corepressor directly with SRC family coactivators in positive regulation of ERalpha-dependent gene expression and, taken with the positive correlation found for SMRT and SRC-3 in human breast tumors, suggest that SMRT can promote ERalpha- and SRC-3-dependent gene expression in breast cancer.

• Authors: Sudipan Karmakar, Tong Gao, Margaret C Pace, Steffi Oesterreich, Carolyn L Smith
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 24 Issue 6 Pg. 1187-202 (Jun 2010) ISSN: 1944-9917 [Electronic] United States
• PMID: 20392877 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• NCOA2 protein, human
• Nuclear Receptor Co-Repressor 2
• Nuclear Receptor Coactivator 2
• Receptors, Progesterone
• Cyclin D1
• Estradiol
• Nuclear Receptor Coactivator 3

Topics

• Breast Neoplasms (genetics)
• Cell Line, Tumor
• Cyclin D1 (genetics, metabolism)
• Enhancer Elements, Genetic (genetics)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Nuclear Receptor Co-Repressor 2 (chemistry, deficiency, metabolism)
• Nuclear Receptor Coactivator 2 (metabolism)
• Nuclear Receptor Coactivator 3 (genetics, metabolism)
• Protein Binding (drug effects)
• Protein Structure, Tertiary
• Receptors, Progesterone (genetics, metabolism)
• Transcription, Genetic (drug effects)
• Transcriptional Activation (drug effects, genetics)