Abstract
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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cyclin D1 / biosynthesis
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Cyclin D1 / genetics
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Estradiol / pharmacology
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Estrogen Antagonists / pharmacology
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism*
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Estrogens / pharmacology
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Gene Knockdown Techniques
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Nuclear Receptor Co-Repressor 2 / genetics
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Nuclear Receptor Co-Repressor 2 / metabolism
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Protein Structure, Tertiary / physiology
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Proto-Oncogene Proteins c-myc / biosynthesis
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Proto-Oncogene Proteins c-myc / genetics
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Receptors, Progesterone / biosynthesis
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Receptors, Progesterone / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Tamoxifen / analogs & derivatives
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Tamoxifen / pharmacology
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology*
Substances
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CCND1 protein, human
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ESR1 protein, human
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Estrogen Antagonists
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Estrogen Receptor alpha
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Estrogens
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GPS2 protein, human
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Intracellular Signaling Peptides and Proteins
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MYC protein, human
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NCOR2 protein, human
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Nuclear Receptor Co-Repressor 2
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Proto-Oncogene Proteins c-myc
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Receptors, Progesterone
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Repressor Proteins
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Tamoxifen
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Cyclin D1
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Estradiol