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Molecular and Cellular Biology, January 2004, p. 362-376, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.362-376.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role for BRG1 in Cell Cycle Control and Tumor Suppression

Kristin B. Hendricks, Frances Shanahan, and Emma Lees*

DNAX Research Inc., Palo Alto, California 94304-1104

Received 28 July 2003/ Returned for modification 2 September 2003/ Accepted 15 September 2003

Human BRG1, a subunit of the Swi/Snf chromatin remodeling apparatus, has been implicated in regulation of cellular proliferation and is a candidate tumor suppressor. Reintroduction of BRG1 into a breast tumor cell line, ALAB, carrying a defined mutation in the BRG1 gene, induced growth arrest. Gene expression data revealed that the arrest may in part be accounted for by down-regulation of select E2F target genes such as cyclin E, but more dramatically, by up-regulation of mRNAs for the cyclin-dependent kinase inhibitors p21 and p15. Protein levels of both p15 and p21 were induced, and p21 protein was recruited to a complex with cyclin-dependent kinase, CDK2, to inhibit its activity. BRG1 can associate with the p21 promoter in a p53-independent manner, suggesting that the induction of p21 by BRG1 may be direct. Further, using microarray and real-time PCR analysis we identified several novel BRG1-regulated genes. Our work provides further evidence for a role for BRG1 in the regulation of several genes involved in key steps in tumorigenesis and has revealed a potential mechanism for BRG1-induced growth arrest.

* Corresponding author. Mailing address: DNAX Research Inc., 901 California Ave., Palo Alto, CA 94304. Phone: (650) 496-1257. Fax: (650) 496-1200. E-mail: emma.lees{at}dnax.org.

Molecular and Cellular Biology, January 2004, p. 362-376, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.362-376.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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