"DESCRIPTION (provided by applicant): Mechanism of p53-dependent tumor suppression Summary P53 tumor suppressor is activated in response to stress signals, including DNA damage and hypoxia. Upon activation, p53 induces a plethora of pro-survival and pro-apoptotic genes as well as the ones that in turn modulate p53 expression and activity. Among these is p21, a cyclin-dependent kinase inhibitor that mediates p53 to induce cell cycle arrest. Previously, we found that RNPC1, also called Rbm38 and a RNA- binding protein, is transcriptionally regulated by DNA damage in a p53-dependent manner. Interestingly, we found that RNPC1 directly binds to p21 transcript and enhances p21 mRNA stability. In addition, RNPC1 binds to p53 transcript and suppresses p53 mRNA translation. Thus, we identified p53-RNPC1 as a novel feedback loop in the p53 pathway. The significance of the loop is exemplified by our recent observations: (1) RNPC1 may play a central role in transmitting signals from Akt-GSK3 kinases and Wip1 -/- protein phosphatase to the p53 pathway and (2) RNPC1 MEFs are prone to premature senescence in a p53- -/- dependent manner and RNPC1 mice are prone to premature aging. These observations prompt us to hypothesize that the p53-RNPC loop plays a key role in p53-mediated tumor suppression and longevity, which represents the central hypothesis to be tested in this renewal application. To test this, the following specific aims are proposed: Aim 1 to determine whether Rbm24, a member of the RNPC family, plays a role in the p53 pathway; Aim 2 to determine how phosphorylation modulates RNPC1 to regulate p53 mRNA translation; and Aim 3 to determine whether RNPC1 plays a role in tumor suppression and premature aging in a p53-dependent manner. " |