Convergence of data from biology and medicine has implicated p53 in the suppression of a wide range of human cancers. In collaboration with the investigator's colleague Daniel Caput of Sanofi, they have characterized p73, protein with considerable homology to the transcriptional activation, DNA binding, and oligomerization domains of p53. Significantly, the human p73 gene is located at chromosome 1p36.3, a region frequently deleted in human cancers such as neuroblastoma, colonrectal carcinoma, ductile breast carcinoma, and melanoma. The investigators' initial studies have shown that p73 interacts with p53 and can transactivate p53 target genes. However, p73 apparently differs from p53 in that it is not induced by radiation and genotoxic drugs, which activate p53. Therefore it is likely that p73 functions cannot be simply extrapolated from those attributed to p53. As many of p53's functions have been realized through the analysis of its loss of function, the investigator has generated mice lacking one or both copies of p73 through targeted disruption and has found that, unlike p53 deficient mice, those lacking p73 show profound defects in growth, development of the nervous system, and function of the immune system. The investigators will use these mice and cell lines derived from them to ask what role p73 plays in proliferation, cell cycle control, and regulation of the immune system. The investigators will further assess the physiological significance of p73 and p53 interactions by analyzing mice deficient in both genes for effects on tumorigenesis and developmental control In addition, they will generate mouse strains with combined defects in p73 and other genes implicated in 1p36-associated tumors, specifically the APC gene in colon cancer, p16INK4 in malignant melanoma, and N-Myc overexpression in neuroblastoma. These experiments aim to take full advantage of the murine system for assaying the effects of a specific and defined set of genetic lesions, and should allow them to probe the interactions of p73 with other genes in pathways of tumorigenesis. Together with their ongoing analysis of human tumors, these murine models should offer important insights into p73 function in development and human disease.
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