Huntington Interacting Protein-1(HIP1) and the Promotion of Neoplasia

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， 由于与亨廷顿蛋白的相互作用， 在亨廷顿病中发生了突变它也与白血病有关，因为我们发现 一种致癌的HIP1/PDGF R融合蛋白，由t（5; 7）染色体易位引起， 患有慢性粒单核细胞白血病的患者（Ross等人，1998年）。我们假设HIP1 与肿瘤发生有关还有几个原因。首先， HIP1/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，表达A HIP1的显性负突变或HIP1的遗传缺失导致几种细胞凋亡 包括肿瘤细胞的类型（Rao等人，2002年和2003年）。第四，HIP1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 将它们转换（Rao等人，2003年）。我们要检验的第一个假设是， HIP1突变类型（编码、剪接或过表达）在体内转化原代细胞。作为 作为推论，我们预测当HIP1不表达时， 癌症在体内的发展。第二，将确定是否存在已知的唯一不足 HIP1的哺乳动物同源物，HIP1相关（HIP1r），改变HIP1在肿瘤发生中的作用。 使用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的缺失 表达将抑制HIP1介导的转化，HIP1r表达的获得将 促进HIP1介导的转化。第三，我们建议研究HIP 1及其 突变体形式改变内吞、肌动蛋白和信号转导途径， 增殖

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.