MODULATORS AND EFFECTORS OF MDM2 AND P53

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DESCRIPTION: (Adapted from the investigator's abstract) The p53 protein plays a critical role in tumor suppression, and represents a pivotal mediator of cellular response to physiological stress. One of the major regulators of p53 activity and abundance is the MDM2 oncoprotein. The long-term goals of this research are to better understand the complex regulation of the p53 tumor suppressor and the MDM2 oncogene, specifically regarding interacting factors that modulate p53 function. In normal cells, p53 has a short half-life and its abundance is low. In response to cellular stress, p53 becomes stabilized and activated as a transcription factor, and the expression levels of p53-target genes increase of decrease. The physiological outcome of such p53 activation is growth arrest or cell death (apoptosis). Thus, elucidation of the parameters that control p53 abundance and function in a cell remains an important area of study in cancer biology. They have identified two proteins that can regulate the activity and stability of p53 when bound. One of these factors, the co-repressor mSin3A (Sin3), was previously determined by them to be a critical mediator of p53-dependent trans-repression and apoptosis. Thus, p53 transcriptional repression activity and stabilization may be functionally linked. The other factor, MDMX, is a homologue of the MDM2 oncoprotein. While MDMX stabilizes p53 by interfering with MDM2-mediated degradation of p53, Sin3 appears to stabilize p53 by a novel mechanism, not dependent on MDM2. The broad aims of this proposal are to elucidate the mechanisms whereby interaction with MDMX and Sin3 influence p53 regulation. Significantly, they have found that Sin3 can bind the p53 homologue p73 as well. This indicates that transcriptional repression and stabilization by interaction with Sin3 may be conserved properties of the family of p53-related transcription factors, with implications for understanding pathways of apoptosis. Therefore, as a natural corollary to this work, this hypothesis will also be tested.