Function of the alternatively spliced p53 gene

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The human p53 gene is among the most intensely studied because it is the prototype tumor suppressor gene. p53 is considered the prototype tumor suppressor because genetically engineered p53 null knockout mice acquire multiple tumors very early in life but are otherwise normal, human families with germline mutations in the p53 gene are highly cancer prone, and p53 is the most common mutated gene in human cancers. Interestingly, most tumors express mutant forms of p53 as opposed to loss of p53 expression and the reason for this remains poorly understood. The p53 protein is a DNA binding transcriptional transactivator that mediates the expression of cellular genes whose products impair the cell cycle and induce apoptosis. Loss of normal cellular p53 function favors tumorigenesis and also renders tumor cells resistant to chemo- and radiotherapy. With the support of NSERC during our last funding period, we discovered that alternative splicing of the human p53 gene results in the expression of a N-terminal truncated form of p53 termed deltaNp53(p47) which is capable of interacting with and inhibiting the full length p53. A major question to be addressed in this proposal is whether deltaNp53(p47) behaves similar to tumor derived mutant p53 and more generally what is the function of deltaNp53(p47). This research could provide a better understanding of why many tumors express a mutant p53.