HIP1 and the Promotion of Neoplasia

描述（由申请人提供）：亨廷顿蛋白相互作用蛋白1 （HIP1）是一种网格蛋白和肌醇脂结合蛋白，可能通过与亨廷顿病中突变的蛋白质亨廷顿蛋白相互作用参与神经退行性变。在慢性髓单细胞白血病（CMML）患者中发现了t（5;7）染色体易位导致的致癌HIP1/PDGFbetaR融合蛋白，这也与白血病有关。我们假设HIP1参与肿瘤发生有三个额外的原因。首先，HIP1/PDGFbetaR融合蛋白的HIP1部分是细胞转化所必需的。其次，HIP1在多个肿瘤中过表达（初步数据部分）。第三，HIP1显性负突变体的表达（初步数据部分）或HIP1基因缺失导致细胞凋亡。我们提出要验证的第一个假设是hip1是致瘤性的，它在体内的过度表达导致癌症。因此，我们预测，当HIP1不表达时，癌症发展的易感性就会降低。其次，我们提出验证HIP1r在内吞作用、细胞生长和癌变中补充HIP1功能的假设。最后，我们提出验证HIP1和HIP1r调节网格蛋白介导的运输导致生长因子受体（GFR）信号传导增加的假设。我们认为这可能是通过增加细胞表面受体的数量来增加对生长因子的敏感性，从而促进细胞的存活和/或生长。

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.