In vivo functions of possible tumor suppressor Dab2

可能的肿瘤抑制因子 Dab2 的体内功能

• 批准号: 6893476
• 负责人: Jonathan A Cooper
• 金额: $ 1.09万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893476
• 关键词: vivo; functions; possible; tumor; suppressor

DESCRIPTION (provided by applicant): The Disabled-2 (Dab2) gene has been proposed to function as a tumor suppressor because it is commonly down-regulated in human ovarian and mammary carcinomas and over-expression can inhibit carcinoma growth. However, mutations in the Dab2 gene have not been detected in human cancers and the true roles of Dab2 in normal cells are unknown. To determine the mechanisms of Dab2 functions in normal cells, we have been investigating Dab2 protein localization, phosphorylation and interactions, and determining the functions of Dab2 during mouse development. Dab2 is expressed in 2 protein forms, p96 and p67. Preliminary studies show that the p96 Dab2 protein is phosphorylated by MAP kinase, localized to clathrin-coated pits and binds to a non-muscle myosin implicated in endocytosis. p96 Dab2 also associates with the cytoplasinic tails of lipoprotein receptors. Indeed, our conditional knockout mice that lack Dab2 show kidney defects similar to those of mice lacking the lipoprotein receptor, megalin. Thus we hypothesize that Dab2 normally regulates megalin traffic. The Dab2 gene has another important function during early post-implantation development. Dab2 mutant embryos have a defect in the extraembryonic visceral endoderm. The phenotype suggests reduced signaling by Nodal, a TGF beta family member. We propose that Dab2 has at least two functions: one in signaling and one in receptor traffic. These functions may be linked or separate. We will test whether the embryonic and kidney defects are indeed due to reduced signaling and traffic, respectively, and whether the p96 and p67 forms of Dab2 have separate or redundant roles. We will investigate the molecular mechanisms whereby Dab2 regulates traffic, especially the role of myosin VI. We will investigate how Dab2 modulates Nodal/TGFbeta signaling in some cells but not others. We will also investigate the significance of Dab2 phosphorylation in regulating these responses. These studies will provide insights into the molecular mechanisms of action of Dab2 and into the role of a single gene in receptor trafficking and signal transduction.

描述（由申请人提供）：Disabled-2（Dab 2）基因被认为是一种肿瘤抑制基因，因为它通常在人卵巢癌和乳腺癌中下调，过表达可抑制癌生长。然而，在人类癌症中尚未检测到Dab 2基因的突变，Dab 2在正常细胞中的真正作用尚不清楚。为了确定Dab 2在正常细胞中的功能机制，我们一直在研究Dab 2蛋白的定位，磷酸化和相互作用，并确定Dab 2在小鼠发育过程中的功能。Dab 2以两种蛋白质形式表达，p96和p67。初步研究表明，p96 Dab 2蛋白被MAP激酶磷酸化，定位于网格蛋白包被的小凹，并结合到涉及内吞作用的非肌肉肌球蛋白。p96 Dab 2还与脂蛋白受体的胞质尾相关。事实上，我们的条件性敲除小鼠缺乏Dab 2表现出类似于缺乏脂蛋白受体megalin的小鼠的肾脏缺陷。因此，我们假设Dab 2正常调节megalin交通。Dab 2基因在早期植入后发育中具有另一个重要功能。Dab 2突变胚胎的胚外内脏内胚层有缺陷。表型表明Nodal（TGF β家族成员）的信号传导减少。我们认为Dab 2至少有两个功能：一个是信号传导，一个是受体运输。这些功能可以是相互关联的，也可以是相互独立的。我们将测试胚胎和肾脏缺陷是否确实是由于减少信号和交通，分别，以及是否Dab 2的p96和p67形式有单独的或冗余的作用。我们将研究Dab 2调节交通的分子机制，特别是肌球蛋白VI的作用。我们将研究Dab 2如何在某些细胞中调节Nodal/TGF β信号，而不是其他细胞。我们还将研究Dab 2磷酸化在调节这些反应中的意义。这些研究将为深入了解Dab 2的分子作用机制以及单个基因在受体转运和信号转导中的作用提供帮助。