Molecular Oncogenic Properties of Mutant p53

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DESCRIPTION (provided by applicant): This application is proposed to address the molecular oncogenic properties of mutant p53. p53 tumor suppressor is a sequence-specific DNA-binding transcription factor. Wild-type p53 is activated in response to various stress signals, such as DNA damage, oncogene activation, and hypoxia. Following its activation, p53 suppresses damaged cells to proliferate by inducing downstream effects, such as cell cycle arrest and apoptosis. However, mutations in the p53 gene abrogate its transcriptional activity, leading to the uncontrolled proliferation characteristic of tumor cells. As a result, mutations of the p53 gene are selected for in greater than 50% of all human cancers. A vast majority of p53 mutations occur in its DNA-binding domain, rendering p53 defective in its DNA binding and transcriptional activities. This represents the classical loss of function mutation for a tumor suppressor. Interestingly, in addition to loss of function, many p53 mutants obtain additional activities, called gain of function. It is well known that in a cell carrying both wild-type and mutant p53, the mutant p53 acquires its gain of function by forming a heterotetramer with, and inhibiting the activity of, wild-type p53. However, the vast majority of tumor cells, which over-express a mutant p53, do not carry a wild-type p53. Thus, mutant p53 gain of function in these tumor cells must be due to its tumor-promoting activity independent of the inhibition of wild-type p53. To further analyze how mutant p53 obtains its gain of function, the following specific aims are proposed: (1) to determine whether mutant p53 is required for maintaining the transformed phenotypes of tumor cells in evading apoptosis and enhanced potentials in proliferation and invasion; (2) to determine whether various classes of p53 mutants differ in their ability to maintain the transformed phenotypes of tumor cells; and (3) to determine whether mutant p53 still functions as a transcription factor that regulates genes involved in promoting survival or inhibiting anti-growth signals.