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Inhibition of cyclin D1 gene transcription by Brg-1.

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.
AuthorsMahadev 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
JournalCell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 7 Issue 5 Pg. 647-55 (Mar 01 2008) ISSN: 1551-4005 [Electronic] United States
PMID18239461 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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
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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