HIP1 and the Promotion of Neoplasia

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DESCRIPTION (provided by applicant): Huntingtin Interacting Protein 1 (HIP1) is a clathrin and inositol lipid binding protein that may be involved in neurodegeneration by virtue of its interaction with huntingtin, the protein mutated in Huntington's disease. It is also associated with leukemia by discovery of the oncogenic HIP1/PDGFbetaR fusion protein that resulted from a t(5;7) chromosomal translocation in a patient with chronic myelomonocytic leukemia (CMML). We hypothesize that HIP1 is involved in tumorigenesis for three additional reasons. First, the HIP1 portion of the HIP1/PDGFbetaR fusion protein is necessary for cellular transformation. Second, HIP1 is over-expressed in multiple tumors (preliminary data section). Third, expression of a dominant negative mutant of HIP1 (preliminary data section) or genetic deletion of HIP1 leads to apoptosis. The first hypothesis we propose to test is that HIP 1 is tumorigenic and its over-expression in vivo leads to cancer. As a corollary, we predict that when HIP1 is not expressed, there will be a diminished susceptibility to the development of cancer. Second, we propose to test the hypothesis that HIP1r complements HIP1 function(s) in endocytosis, cell growth and carcinogenesis. Finally, we propose to test the hypothesis that regulation of clathrin mediated trafficking by HIP1 and HIP1r results in an increase in growth factor receptor (GFR) signaling. We suggest that this maybe accomplished by increasing the number of the cell surface receptors to increase sensitivity to growth factor and thereby promote cellular survival and/or growth.