The PI has cloned and characterized a novel p53 homolgoue p40 (AIS), one of several variants (p40/51/63/73L) that is encoded by the 3q27-28 gene locus. Although the AIS protein can interact with p53 binding sites and transcriptionally activate downstream targets of p53, the Pi has found no evidence of a tumor suppressor function of AIS. On the contrary, accumulating evidence supports and oncogenic role for this gene. The PI has sown that: (i) the AIS gene is amplified in primary lung cancer and head and neck and cancer squamous cell carcinoma (SCC) cell lines by FISH analysis; (ii) chromosomal amplification of AIS is associated with increased AIS RNA expression and AIS protein accumulation; (iii) the AIS gene product is able to transform Rat1a cells in culture and leads to increased tumor growth in nude mice; (iv) AIS interacts with p53 in vitro and in vivo, and suppressed p53-mediated transactivation activity on target genes. The PI now proposes to examine in depth the role of AIS in human cancer. The PI will study AIS activation in the progression of SCC of the HN and lung and other human tumors. Since AIS is a putative transcription factor the PI will identify the downstream targets of AIS by novel assays. The PI will seek to identify the transcriptional binding site of AIS using yeast genetic strategies in order to clarify the target sites involved in cell proliferation, oncogenesis and apoptosis. Finally, based on results from the PI that p53 associates with AIS in vitro and in vivo, the nature of this protein-protein interaction will be characterized. These studies will yield new insights into the oncogenic activity of AIS and will allow further elucidation of its function in human tumorigenesis.
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