HIP1 and the Promotion of Neoplasia

描述(申请人提供)：亨廷顿蛋白相互作用蛋白1(HIP1)是一种网状蛋白和肌醇脂质结合蛋白，可能通过与亨廷顿病突变的亨廷顿蛋白相互作用而参与神经退行性变。在慢性粒单核细胞白血病(CMML)患者中发现致癌的HIP1/PDGFbetaR融合蛋白，导致t(5；7)染色体易位，也与白血病有关。我们假设HIP1参与肿瘤的发生还有另外三个原因。首先，HIP1/PDGFbetaR融合蛋白的HIP1部分是细胞转化所必需的。第二，HIP1在多发性肿瘤中高表达(初步数据部分)。第三，HIP1的显性负性突变体(初步数据部分)的表达或HIP1的基因缺失会导致细胞凋亡。我们提出的第一个假设是，HIP-1是致癌的，它在体内的过度表达会导致癌症。作为推论，我们预测，当HIP1不表达时，癌症发生的易感性将会降低。其次，我们建议检验HIP1r补充HIP1在内吞、细胞生长和癌变中的功能的假说(S)。最后，我们建议检验这一假说，即通过HIP1和HIP1r调节clathrin介导的转运导致生长因子受体(GFR)信号的增加。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.