Inhibition of cyclin D1 gene transcription by Brg-1

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

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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 HP1α/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.

Original languageEnglish
Pages (from-to)647-655
Number of pages9
JournalCell Cycle
Volume7
Issue number5
Publication statusPublished - 01-03-2008

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Rao, M., Casimiro, M. C., Lisanti, M. P., D'Amico, M., Wang, C., Shirley, L. A., Leader, J. E., Liu, M., Stallcup, M., Engel, D. A., Murphy, D. J., & Pestell, R. G. (2008). Inhibition of cyclin D1 gene transcription by Brg-1. Cell Cycle, 7(5), 647-655.