Huntingtin Interacting Protein 1 (HIP1) is a clathrin, actin and inositol lipid binding protein that has been implicated in neurodegeneration by virtue of its interaction with huntingtin, the protein mutated in Huntington's disease. It is also associated with leukemia by our discovery of the oncogenic HIP1/PDGF?R fusion protein that resulted from a t(5;7) chromosomal translocation in a patient with chronic myelomonocytic leukemia (Ross et al., 1998). We hypothesize that HIP1 is involved in tumorigenesis for several additional reasons. First, the HIP1 portion of the HIP1/PDGF?R fusion protein is necessary for cellular transformation (Ross and Gilliland, 1999). Second, HIP1 is upregulated in multiple tumors (Rao et al., 2002). Third, expression of a dominant negative mutant of HIP1 or genetic deletion of HIP1 leads to apoptosis in several cell types including tumor cells (Rao et al., 2002 and 2003). Fourth, HIP1 deficiency inhibits prostate tumorigenesis (Bradley et al., 2005) and finally, overexpression of HIP1 in fibroblasts transforms them (Rao et al., 2003). The first hypothesis we propose to test is that different types of HIP1 mutations (coding, splicing or over-expression) transform primary cells in vivo. As a corollary, we predict that when HIP1 is not expressed, there will be a diminished susceptibility to the development of cancer in vivo. Second, will determine if the deficiency of the only known mammalian homologue of HIP1, HIP1-related (HIP1r), modifys HIP1's role in tumorigenesis. Using mice with targeted mutations in HIP1 and HIP1r, we have found that HIP1 and HIP1r compensate for one another (preliminary data section). We therefore predict that loss of HIP1r expression would inhibit HIP1 mediated transformation and gain of HIP1r expression would promote HIP1 mediated transformation. Third, we propose to investigate how HIP1 and its mutant forms change endocytic, actin and signal transduction pathways to promote neoplastic proliferation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA098730-09
Application #
8205025
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mufson, R Allan
Project Start
2003-07-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
9
Fiscal Year
2012
Total Cost
$282,326
Indirect Cost
$104,389
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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