Cell Transformation by Dbl-like onco-proteins

Dbl 样癌蛋白的细胞转化

• 批准号: 6758616
• 负责人: DANNY MANOR
• 金额: $ 24.76万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758616
• 关键词: G protein; athymic mouse; biological signal transduction; cell proliferation; enzyme activity; fibroblasts; guanine nucleotide binding protein; guanosinetriphosphatases; neoplastic transformation; oncoproteins; protein kinase; protein localization; protooncogene; tissue /cell culture

DESCRIPTION (provided by applicant): The Dbl oncogene product was originally identified as the transforming gene from human diffuse B- cell lymphoma. It is now evident that Dbl is only one member of a growing family of cellular proteins that contain a unique structural 'signature': the tandem arrangement of pleckstrin homology (PH) and Dbl homology (DH) domains. Mutated versions of most DbI- like genes were identified as causing a variety of human malignant and invasive pathologies, suggesting a key role for these molecules in regulation of normal cell growth. To date, only one biochemical activity has been associated with Dbl- related proteins, namely to serve activators of (cause GTP binding to) low Mw GTP- binding proteins from the Rho- subfamily, such as Rho, Cdc42 and Rac. It is generally hypothesized that the basis for the oncogenic capability exhibited by Dbl molecules is an outcome of their ability to cause GTPase activation. In accordance with this hypothesis, activated alleles of Cdc42, Rac and Rho proteins were demonstrated to possess growth- regulatory properties. The proposed research aims at gaining a better understanding of the molecular mechanisms that underlie Dbl- induced transformation of mammalian cells. Two specific avenues of investigation will be pursued that constitute the specific aims of this proposal. These aims are: 1) To understand how the activity of proto- Dbl is regulated in normal (non-transformed) cells. We propose to address the roles of interacting proteins, intra-cellular localization and phosphorylation events in regulating the growth- promoting signals originating from proto- Dbl. 2) To understand the down-stream signaling pathway that leads from activation of Cdc42 by Dbl to oncogenic transformation. We propose to identify a novel target of Cdc42 that is a likely candidate for mediating Dbl- transformation signals and to characterize the signaling pathway that originates from Dbl and leads to stimulation of survival pathways via activation of PDK1 and Akt.

描述（由申请人提供）：DBL致癌基因最初被鉴定为人类弥漫性B-细胞淋巴瘤的转化基因。现在很明显，DBL只是不断增长的细胞蛋白家族的一个成员，其中包含独特的结构“签名”：Pleckstrin同源性（pH）和DBL同源性（DH）域的串联布置。大多数类似基因的突变版本被确定为引起各种人类恶性和侵入性病理，这表明这些分子在调节正常细胞生长中的关键作用。迄今为止，只有一种生化活性与DBL相关蛋白有关，即为Rho，Cdc42和RAC等Rho-fiminy的（引起GTP结合）的激活剂（引起GTP结合）低MW GTP结合蛋白。通常认为，DBL分子表现出的致癌能力的基础是它们引起GTPase激活的能力的结果。根据这一假设，证明Cdc42，RAC和RHO蛋白的活化等位基因具有生长调节特性。拟议的研究旨在更好地了解基于DBL诱导哺乳动物细胞转化的分子机制。将采用两种具体的调查途径，构成该提案的具体目的。这些目的是：1）了解如何在正常（未转化）细胞中调节原始DBL的活性。我们建议解决相互作用的蛋白质，细胞内定位和磷酸化事件在调节源自原始DBL的生长信号中的作用。 2）了解从DBL激活Cdc42到致癌转化的下游信号通路。我们建议确定一个新的CDC42目标，该目标可能是介导DBL转化信号的候选者，并表征源自DBL并通过激活PDK1和AKT的刺激生存途径的信号传导途径。