Abstract
Multiple tumor-suppressor mechanisms exist to promote genomic stability. One such mechanism is cellular senescence. In response to DNA damage and oncogenic stimuli, the senescence program, including the p53 and Rb pathways, is activated to prevent the proliferation of damaged cells and their potential oncogenic transformation.
We are performing a pooled whole genome shRNA screen in primary human fibroblasts to identify novel components of the senescence machinery. In addition to many known senescence regulators including cell cycle and DNA damage response factors, we have also uncovered many genes of unknown function. From this screen we have identified SWI/SNF components BRD7 and BAF180 as novel regulators of replicative and oncogene-induced senescence.
Both BRD7 and BAF180 are required for p53 transcriptional activity toward a subset of target genes including p21, and BRD7 physically interacts with p53. Overexpression of BRD7 induces premature senescence and p21 expression, highlighting its regulatory role in this pathway. We also show that BRD7 is required for expression of p21 in p53-independent contexts, such as in response to TGF-β and 1α,25(OH)2D3 (vitamin D) in epithelial cells. Lastly, BRD7 and BAF180 are deletion targets in human cancer, suggesting that their loss may provide additional mechanisms to antagonize p53 function in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A33.
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