Huntington Interacting Protein-1(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、肌动蛋白和肌醇脂质结合蛋白，由于其与亨廷顿病中突变的亨廷顿蛋白的相互作用而与神经退行性变有关。我们发现的致癌HIP1/PDGF？R融合蛋白也与白血病有关，这种融合蛋白是由慢性粒单核细胞白血病患者的t(5；7)染色体易位引起的(Ross等人，1998年)。我们假设HIP1参与肿瘤的发生还有其他几个原因。首先，HIP1/PDGF？R融合蛋白的HIP1部分是细胞转化所必需的(Ross和Gillland，1999)。其次，HIP1在多发性肿瘤中上调(Rao等人，2002年)。第三，HIP1的显性负性突变体的表达或HIP1的基因缺失会导致包括肿瘤细胞在内的几种细胞类型的凋亡(Rao等人，2002年和2003年)。第四，HIP1缺乏抑制了前列腺癌的发生(Bradley等人，2005年)，最后，HIP1在成纤维细胞中的过表达改变了它们(Rao等人，2003年)。我们提出的第一个假设是，不同类型的HIP1突变(编码、剪接或过度表达)在体内改变了原代细胞。作为推论，我们预测，当HIP1不表达时，体内发生癌症的易感性将会降低。第二，将确定唯一已知的哺乳动物HIP1同源基因HIP1相关(HIP1r)的缺失是否改变HIP1在肿瘤发生中的S作用。使用具有HIP1和HIP1r靶向突变的小鼠，我们发现HIP1和HIP1r相互补偿(初步数据部分)。因此，我们预测HIP1r表达的缺失将抑制HIP1介导的转化，而HIP1r表达的获得将促进HIP1介导的转化。第三，我们建议研究HIP1及其突变形式如何改变内细胞、肌动蛋白和信号转导途径来促进肿瘤增殖。

DESCRIPTION (provided by applicant): 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.