Huntington Interacting Protein-1(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（HIP 1）是网格蛋白、肌动蛋白和肌醇脂质结合蛋白，由于其与亨廷顿蛋白（在亨廷顿病中突变的蛋白质）的相互作用而与神经变性有关。它也与我们发现的致癌HIP 1/PDGF？R融合蛋白，该融合蛋白由慢性粒单核细胞白血病患者的t（5;7）染色体易位产生（Ross等人，1998年）。我们假设HIP 1参与肿瘤发生还有其他几个原因。首先，HIP 1/PDGF？R融合蛋白是细胞转化所必需的（Ross和Gilliland，1999）。其次，HIP 1在多种肿瘤中上调（Rao et al.，2002年）。第三，HIP 1的显性失活突变体的表达或HIP 1的遗传缺失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，HIP 1缺陷抑制前列腺肿瘤发生（布拉德利等人，2005），最后，成纤维细胞中HIP 1的过表达使它们转化（Rao等人，2003年）。我们提出的第一个假设是，不同类型的HIP 1突变（编码，剪接或过表达）在体内转化原代细胞。作为推论，我们预测当HIP 1不表达时，体内癌症发展的易感性将降低。第二，将确定是否缺乏唯一已知的哺乳动物同源的HIP 1，HIP 1相关（HIP 1 r），修改HIP 1的作用，在肿瘤发生。使用HIP 1和HIP 1 r靶向突变的小鼠，我们发现HIP 1和HIP 1 r相互补偿（初步数据部分）。因此，我们预测HIP 1 r表达的丧失将抑制HIP 1介导的转化，而HIP 1 r表达的获得将促进HIP 1介导的转化。第三，我们建议研究HIP 1及其突变形式如何改变内吞，肌动蛋白和信号转导途径，以促进肿瘤增殖。

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.