Role for BRG1 in Cell Cycle Control and Tumor Suppression

Abstract

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.

We thank members of the McClanahan laboratory for assistance with the microarray experiments, members of the DNAX Protein Reagent Group for large-scale production and purification of the adenoviruses, and Canji for AdRB, Adp53, and Adp21. We thank Scott Frank, David Parry, and Anne Rascle for critical reading of the manuscript and helpful discussions.

DNAX Research Inc. is supported by Schering Plough Corporation.