MUTANT P53 GAIN OF FUNCTION IN TUMORIGENESIS

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The p53 tumor suppressor gene is the most frequently mutated gene in human cancer and tumors that express mutant p53 may be associated with a worse prognosis than p53-null cancers. The long-term goal of this research proposal is to further our understanding of the function of mutant p53 in tumorigenesis. Mutant p53 enhances the tumorigenic potential of p53-negative cell lines and this activity correlates with its ability to selectively transactivate the human multi-drug resistance (MDR1) promoter. In our previous funding period, we established that: 1) mutant p53 can regulate expression of the endogenous MDR1 gene as well as the endogenous c-myc gene; 2) mutant p53 transactivation of the c-myc promoter is mediated by sequences located downstream from the transcription start site; 3) the mutant p53 response element in the c-myc gene is not an enhancer and exhibits position and orientation dependent function; and 4) mutant p53 transactivation requires the C-terminal domain, which binds RNA and single-strand (ss) DNA. These results lead to a testable hypothesis that mutant p53 functions in transactivaion through an RNA-dependent mechanism that may be similar to the model proposed for the regulation of the human immunodeficiency virus LTR promoter by the TAT transactivator. To continue our studies on mutant p53 gain of function in tumorigenesis, we propose to address the following specific questions: 1) Does mutant p53 accelerate tumorigenesis in vivo; 2) What is the role of the C- terminus of mutant p53 in gain of function; 3) What is the nature of the mutant p53 response element in the c-myc and MDR1 promoters; and 4) Does mutant p53 function in transactivation and tumorigenicity through an RNA dependent mechanism? Our findings demonstrate significant differences in the structural requirements for wild-type and mutant p53 function, which may provide an exploitable basis for developing therapeutic approaches to treating cancer. The studies proposed here will build on these observations and contribute to our understanding of how mutation of p53 enhances cell growth and tumorigenicity.