The retinoblastoma tumor suppressor, RB, is inactivated in-the majority of human cancers, resulting in growth advantage. While the underlying basis of inactivation encompasses a variety of mechanisms (e.g. deregulated phosphorylation, direct oncoprotein binding, point mutation) all of these result in the disruption of RB assembled complexes. When active, RB is hypophosphorylated and assembles transcriptional repressor complexes to facilitate repression of critical cell cycle genes. Mitogenic signaling cascades or oncogenic lesions stimulate the phosphorylation of RB, thereby disrupting the transcriptional repressor complexes and enabling cell cycle progression. In contrast, anti-mitogenic signals (e.g. DNA-damage) will prevent phosphorylation and maintain RB-repressor complexes to inhibit cellular proliferation. Therefore, understanding RB-mediated transcriptional repression is germane both to regulated cell cycle progression (i.e. the interplay of mitogenic and anti-mitogenic signaling) and tumorigenesis. RB mediates transcriptional repression by recruiting co-repressors to target promoters. These co-repressors have specific affects on chrornatin leading to direct modification of histories (e.g. methylation or deacetylation). Since transcriptional repression is critical for RB function, loss of co-repressors could represent a means through which RB is functionally inactivated in cancer. Of the RB associated co-repressors, SWI/SNF proteins have been implicated as a tumor suppressor through a combination of genetic studies in cell lines, mouse models and expression analysis in primary human tumors. Consistent with the idea that loss of this co-repressor complexes compromise RB signaling, we have found that loss of the core SWI/SNF ATPases (BRG1 and BRM) bypass RB-mediated transcriptional repression and cell cycle inhibition. Therefore, we will test the hypothesis that BRG1/BRM plays a specific role in mediating RB-dependent transcriptional repression to suppress uncontrolled proliferation and tumorigenesis. Specifically, we will (I) determine the mechanism through which BRG1/BRM facilitate the action of RB in transcriptional repression, (11) define the targets of specific RB co-repressor complexes, and (111)specifically elucidate the role of BRG1/BRM and transcriptional repression in RB-dependent tumor suppression.
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