BRG1 Controls the Activity of the Retinoblastoma Protein via Regulation of p21^{CIP1/WAF1/SDI}

Abstract

The ubiquitous mammalian chromatin-remodeling SWI/SNF-like BAF complexes play critical roles in tumorigenesis. It was suggested that the direct interaction of BRG1 with the retinoblastoma protein pRB is required for regulation of cell cycle progression by pRB. We present evidence that the BRG1-containing complexes regulate the expression of the cdk inhibitor p21^{CIP1/WAF1/SDI}. Furthermore, we show that the physical interaction between BRG1 and pRB is not required for induction of cell growth arrest and transcriptional repression of E2F target genes by pRB. Instead, BRG1 activates pRB by inducing its hypophosphorylation through up-regulation of the cdk inhibitor p21. The hypophosphorylation of pRB is reinforced by down-regulation of critical components, including cdk2, cyclin E, and cyclin D, in the pRB regulatory network. We demonstrate that up-regulation of p21 by BRG1 is necessary to induce formation of flat cells, growth arrest, and finally, cell senescence. Our results suggest that the BRG1-containing complexes control cellular proliferation and senescence by modulating the pRB pathway via multiple mechanisms.

We thank Tian Chi, Gerald R. Crabtree, Warren J. Leonard, David Levens, Mimi Wan, and Carl Wu for critical reading of the manuscript. K.Z. thanks Warren Leonard for continuous encouragement and support.

This work was supported by intramural grants to NHLBI, NIH.