Inhibition of cyclin D1 gene transcription by Brg-1.
The evolutionarily conserved SWI-SNF chromatin remodeling complex regulates cellular proliferation. A catalytic subunit, BRG-1, is frequently down regulated, silenced or mutated in malignant cells, however, the mechanism by which BRG-1 may function as a tumor suppressor or block breast cancer cellular proliferation is not understood. The cyclin D1 gene is a collaborative oncogene overexpressed in greater than 50% of human breast cancers. Herein, BRG-1 inhibited DNA synthesis and cyclin D1 expression in human MCF-7 breast cancer epithelial cells. The cyclin D1 promoter AP-1 and CRE sites were required for repression by BRG-1 in promoter assays. BRG-1 deficient cells abolished and siRNA to BRG-1 reduced, formation of the BRG-1 chromatin complex. The endogenous cyclin D1 promoter AP-1 site bound BRG-1. Estradiol treatment of MCF-7 cells induced recruitment of BRG-1 to the endogenous hpS2 gene promoter. Estradiol, which induced cyclin D1 abundance, was associated with a reduction in recruitment of the co-repressors HP1alpha/HDAC1 to the endogenous cyclin D1 promoter AP-1/BRG-1 binding sites. These studies suggest the endogenous cyclin D1 promoter BRG-1 binding site functions as a molecular scaffold in the context of local chromatin upon which coactivators and corepressors are recruited to regulate cyclin D1.
Rao
Mahadev
M
Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Casimiro
Mathew C
MC
Lisanti
Michael P
MP
D'Amico
Mark
M
Wang
Chenguang
C
Shirley
L Andrew
LA
Leader
Jennifer E
JE
Liu
Manran
M
Stallcup
Michael
M
Engel
Daniel A
DA
Murphy
Daniel J
DJ
Pestell
Richard G
RG
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000090266:Chromobox Protein Homolog 5; D019938:Cyclin D1 / Q000235:genetics*; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
C000715594:CBX5 protein, human; D004273:DNA, Neoplasm; D050505:Mutant Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000090266:Chromobox Protein Homolog 5; D019938:Cyclin D1; C084108:SMARCA4 protein, human; D004265:DNA Helicases