Mutations of the p53 tumor suppressor gene are the most frequent genetic lesion in breast cancer, suggesting a critical role for normal p53 protein in regulating mammary cell growth. The p53 mutations observed in various cancers have been shown to alter the biochemical functions of the p53 protein; however, it is not known which p53 functions are critical for its role in breast oncogenesis. Using the E6 oncogene of the human papilloma virus 16 (HPV16), they demonstrated that the loss of p53 protein was essential for immortalization of mammary epithelial cells (MECs). Recently, they have identified three p53 mutants, del239, R175H and R249S, which themselves are capable of inducing MEC immortalization, providing a unique system to delineate the p53 functions that are critical for MEC immortalization. Here, they propose analyses to elucidate the biochemical basis of mutant p53-induced MEC immortalization. Toward this goal we will (i) delineate the structural requirements for mutant p53-induced MEC immortalization by assessing the immortalizing ability of specific p53 mutants that alter its binding and transcriptional activation domains, (ii) analyze the effects of p53 mutants on p53-mediated transcriptional activation, repression, G1 arrest, and apoptosis. (iii) examine the in vivo association of p53 mutants with known cellular binding proteins. In particular, they propose to determine the primary structure of a del239 mutant-specific cellular binding protein p50 and to ascertain its role in mutant p53-induced immortalization. These studies, designed to identify the specific p53 functions that are targeted by immortalizing p53 mutants, should lead to a better understanding of how wild-type p53 controls normal MEC growth and how p53 mutations may contribute to the evolution of human breast cancer. Identification of novel targets of p53 function and oncogenesis in breast cells should be an important first step toward design of novel molecular therapeutics.
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