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

Sudipan Karmakar1, Tong Gao, Margaret C Pace

  • 1Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

Molecular Endocrinology (Baltimore, Md.)
|April 16, 2010
PubMed

Insights

The silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor enhances estrogen receptor-alpha (ERalpha) target gene expression. SMRT cooperates with coactivators like SRC-3, promoting breast cancer gene activity.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Research

Background:

  • Coactivators enhance estrogen receptor-alpha (ERalpha) target gene expression.
  • The role of corepressors in 17beta-estradiol (E2)-induced gene expression is not well understood.
  • Silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) is a corepressor involved in ERalpha activity.

Purpose of the Study:

  • Investigate the role of SMRT corepressor in E2-induced gene expression.
  • Determine the interaction between SMRT and steroid receptor coactivator-3 (SRC-3).
  • Elucidate the mechanism of SMRT and SRC-3 cooperation in ERalpha-dependent gene regulation.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to measure SMRT and SRC-3 recruitment.
  • Co-immunoprecipitation (Co-IP) to assess protein interactions.
  • Gene expression analysis following SMRT or SRC-3 depletion.

Main Results:

  • SMRT is recruited to progesterone receptor (PR) and cyclin D1 gene regulatory regions in an E2-dependent manner.
  • SMRT and SRC-3 directly bind and cooperate to enhance E2-induced PR and cyclin D1 expression.
  • SMRT enhances the transcriptional activity of SRC family coactivators.

Conclusions:

  • SMRT corepressor directly interacts with SRC family coactivators to positively regulate ERalpha-dependent gene expression.
  • The SMRT-SRC interaction promotes ERalpha and SRC-3-dependent gene expression in breast cancer.
  • SMRT and SRC-3 show a positive correlation in human breast tumors, suggesting a role in breast cancer progression.

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