The regulation of mutant p53 protein accumulation in cancer: molecular basis and therapeutic potential

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Abstract Tumor suppressor p53 is the most frequently mutated gene in human cancer, including colorectal cancer (CRC). Many tumor-associated mutant p53 (mutp53) proteins not only lose the tumor suppressive function of wild-type p53, but also gain new oncogenic activities to promote tumorigenesis, which is defined as the “gain-of-function” (GOF). Mutp53 proteins often become stable and accumulate to very high levels in cancer, which is critical for mutp53 GOF in tumorigenesis. Destabilizing mutp53 protein is being actively tested as a novel and promising strategy for cancer therapy. However, the mechanism of mutp53 accumulation in cancer is poorly understood, which hinders the development of effective strategies for cancer therapy. MDM2 is the most critical negative regulator of p53. MDM2 isoform B (MDM2B), a spliced isoform of MDM2, is frequently overexpressed in human cancer, and plays an important role in tumorigenesis. Currently, the mechanisms underlying MDM2B-mediated mutp53 accumulation and MDM2B overexpression in cancer are poorly understood. Identifying their underlying mechanisms has the direct potential to develop effective strategies to treat cancers carrying mutp53. The goal of this study is to determine the mechanism of mutp53 accumulation in CRC to provide novel therapeutic targets/strategies for CRC carrying mutp53. Based on our preliminary studies, we hypothesize that MDM2B overexpression is a critical mechanism underlying mutp53 protein accumulation and GOF in CRC, and furthermore, MDM2B and its signaling pathway can be targeted for therapy in CRC carrying mutp53. We will test our hypothesis by following specific aims: 1) determine whether MDM2B overexpression is a critical mechanism underlying mutp53 accumulation and GOF in CRC using different mouse colorectal tumor models, and identify mechanisms underlying MDM2B-mediated mutp53 accumulation; and 2) identify mechanisms underlying MDM2B overexpression in CRC, and test whether targeting MDM2B and its signaling pathway can inhibit mutp53 accumulation and GOF in CRC. We anticipate that this proposed study will provide new paradigms regarding mutp53 accumulation, tumor-promoting function of MDM2B, and MDM2B overexpression in CRC. If accomplished successfully, results from this study will have potential to develop MDM2B and its signaling pathway as novel therapeutic targets for CRC carrying mutp53.