G protein pathway suppressor 2 (GPS2) is a transcriptional corepressor important for estrogen receptor alpha-mediated transcriptional regulation

J Biol Chem. 2009 Dec 25;284(52):36395-36404. doi: 10.1074/jbc.M109.062109. Epub 2009 Oct 26.


We have identified G protein suppressor 2 (GPS2) as a stable component of the SMRT corepressor complexes. GPS2 potently represses basal transcription, with the repression domain mapped to the N-terminal silencing mediator of retinoic acid and thyroid hormone receptor (SMRT)-interacting domain. Knockdown of GPS2 abrogates, whereas overexpression potentiates, SMRT-mediated repression activity. The SMRT complexes are involved in 4-hydroxyl-tamoxifen (4OHT)-mediated gene repression by estrogen receptor alpha (ERalpha). We show that 4OHT recruits SMRT and GPS2 to the promoter of pS2, an ERalpha target gene, in a dynamic manner. Unexpectedly, we also found that estradiol (E2) promotes promoter recruitment of the SMRT complexes. While knockdown of GPS2 compromised 4OHT-mediated repression, it enhanced E2-induced expression of a reporter gene and several endogenous ERalpha target genes, including pS2, cyclin D1 (CCND1), progesterone receptor (PR), and c-MYC. Finally, we show that depletion of GPS2 or SMRT by siRNA promotes cell proliferation in MCF-7 breast cancer cells. Thus, we concluded that GPS2 is an integral component of the SMRT complexes, important for ligand-dependent gene regulations by ERalpha and a suppressor for MCF-7 cell proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclin D1 / biosynthesis
  • Cyclin D1 / genetics
  • Estradiol / pharmacology
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / pharmacology
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Nuclear Receptor Co-Repressor 2 / metabolism
  • Protein Structure, Tertiary / physiology
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / genetics
  • Receptors, Progesterone / biosynthesis
  • Receptors, Progesterone / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology*


  • CCND1 protein, human
  • ESR1 protein, human
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogens
  • GPS2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • MYC protein, human
  • NCOR2 protein, human
  • Nuclear Receptor Co-Repressor 2
  • Proto-Oncogene Proteins c-myc
  • Receptors, Progesterone
  • Repressor Proteins
  • Tamoxifen
  • Cyclin D1
  • Estradiol