Abstract |
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.
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Authors | Mahadev Rao, Mathew C Casimiro, Michael P Lisanti, Mark D'Amico, Chenguang Wang, L Andrew Shirley, Jennifer E Leader, Manran Liu, Michael Stallcup, Daniel A Engel, Daniel J Murphy, Richard G Pestell |
Journal | Cell cycle (Georgetown, Tex.)
(Cell Cycle)
Vol. 7
Issue 5
Pg. 647-55
(Mar 01 2008)
ISSN: 1551-4005 [Electronic] United States |
PMID | 18239461
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- CBX5 protein, human
- DNA, Neoplasm
- Mutant Proteins
- Nuclear Proteins
- Repressor Proteins
- Transcription Factor AP-1
- Transcription Factors
- Chromobox Protein Homolog 5
- Cyclin D1
- SMARCA4 protein, human
- DNA Helicases
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Topics |
- Cell Line, Tumor
- Chromatin Immunoprecipitation
- Chromobox Protein Homolog 5
- Cyclin D1
(genetics)
- DNA Helicases
(chemistry, metabolism)
- DNA, Neoplasm
(biosynthesis)
- Gene Expression Regulation, Neoplastic
- Humans
- Mutant Proteins
(chemistry, metabolism)
- Nuclear Proteins
(chemistry, metabolism)
- Promoter Regions, Genetic
(genetics)
- Protein Binding
- Repressor Proteins
(metabolism)
- Transcription Factor AP-1
(metabolism)
- Transcription Factors
(chemistry, metabolism)
- Transcription, Genetic
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