G protein pathway suppressor 2 (GPS2) is a transcriptional corepressor important for estrogen receptor alpha-mediated transcriptional regulation.
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.
Department of Biochemistry, School of Medicine, Case Western Reserve University, the Case Comprehensive Cancer Center, and University Hospitals of Cleveland, Cleveland, Ohio 44106.
Xiwen
X
Cheng
Department of Biochemistry, School of Medicine, Case Western Reserve University, the Case Comprehensive Cancer Center, and University Hospitals of Cleveland, Cleveland, Ohio 44106. Electronic address: hxk43@cwru.edu.
Hung-Ying
HY
Kao
D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
C530104:CCND1 protein, human; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; C103316:GPS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D016271:Proto-Oncogene Proteins c-myc; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D013629:Tamoxifen; D019938:Cyclin D1; D004958:Estradiol