10Q TUMOR SUPPRESSOR GENE

10Q肿瘤抑制基因

• 批准号: 2465317
• 负责人: Peter A Steck
• 金额: $ 26.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2465317
• 关键词: athymic mouse; biological signal transduction; carcinoma; chromosome deletion; enzyme mechanism; gene expression; genetic library; genetic manipulation; genetic mapping; glioblastoma multiforme; glioma; human tissue; in situ hybridization; molecular cloning; neoplasm /cancer genetics; neoplastic process; northern blottings; nucleic acid sequence; nucleic acid structure; polymerase chain reaction; prostate neoplasms; protein localization; protein tyrosine phosphatase; radiotracer; tissue /cell culture; transfection; tumor suppressor genes

(Adapted from the investigator's abstract) The initiation and progression of the tumorigenic capabilities of neoplastic cells involves genetic alterations which lead to the activation of oncogenes and the loss of function of tumor suppressor genes. The objective of this project is to identify, confirm, and characterize a tumor-suppressor (TS) gene localized to the long arm of chromosome 10 (10q23-24) that is intimately involved in the progression of gliomas to high grade glioblastoma multiforme (GMB). A strong candidate suppressor gene has recently been identified in the critical region. Deletion of large segments, or an entire copy, of chromosome 10 represents a very frequent (-90 percent) molecular alteration in GBMs and several other cancers. The hypothesis of the study proposes the loss of function of a tumor suppressor gene on chromosome 10 directly contributes to the progression of these cancers. The candidate TS gene cloned at the critical region appears to encode for a novel protein tyrosine phosphatase (PTPase), implicating a potential role of the candidate TS gene in cell signaling. They have previously used a functional approach in microcell-mediated chromosomal transfer to demonstrate the presence and biological function of a TS gene on 10q involved in glioma oncogenesis. To further define the TS locus a series of three independent approaches were pursued to define a critical region, including the identification of homozygous deletions in gliomas cells. All three of the approaches and allelic deletion analysis of prostrate carcinomas directed the attention towards a single locus. A gene has now been cloned from this critical region and spans the homozygous deletions. Mutations to the gene in cultured glioma and prostrate cells along with alterations in several human tumor specimens have been observed. Motif analyses implicates the gene product as a novel PTPase. This proposal is directed at the characterization of the candidate TS gene. The tumor suppressive active of the candidate gene will be assessed by transfecting various constructs of the candidate gene into glioma cells. The mutation and as the possible presence and effect(s) of germline mutations. The proposed biochemical activity(s) of the candidate gene as a protein tyrosine phosphatase will be assessed. Furthermore, the effects of mutations on the proposed activity(s) and/or localization of the gene product will be addressed. Finally, the signaling pathway that the candidate TS gene may play a role in will be examined. This combination of functional and molecular approaches will demonstrate the functional activity of the candidate TS gene and initiate investigations into its mechanism(s) of action.

（根据研究者的摘要改编）的启动和进步 肿瘤细胞的致瘤能力涉及遗传 导致癌基因激活和丧失的改变 肿瘤抑制基因的功能。该项目的目的是 识别，确认和表征肿瘤 - 抑制剂（TS）基因的定位 到密切涉及的10染色体（10q23-24）的长臂 神经胶质瘤向高级胶质母细胞瘤多形（GMB）的进展。一个 最近在 关键区域。删除大细分市场或整个副本 染色体10代表非常频繁（-90％）的分子 GBM和其他几种癌症的改变。研究的假设 提出在染色体10上抑制肿瘤基因的功能丧失 直接有助于这些癌症的进展。候选人TS 克隆在临界区域的基因似乎编码了一种新蛋白 酪氨酸磷酸酶（PTPase），暗示了该磷酸酶的潜在作用 细胞信号传导中的候选TS基因。他们以前曾使用过 微孔介导的染色体转移中的功能方法 展示TS基因在10q上的存在和生物学功能 参与神经胶质瘤肿瘤发生。为了进一步定义TS基因座 采用了三种独立的方法来定义关键区域， 包括鉴定神经胶质瘤细胞中纯合缺失。全部 三种方法和等位基因缺失分析 癌将注意力转向一个基因座。一个基因现在有 从这个关键区域克隆并跨越纯合缺失。 培养的神经胶质瘤和俯卧细胞中基因的突变以及 已经观察到了几个人类肿瘤标本的改变。主题 分析将基因产物视为一种新型PTPase。该提议是 针对候选TS基因的表征。肿瘤 抑制候选基因的活性将通过转染评估 候选基因在神经胶质瘤细胞中的各种构建体。突变 以及作为种系突变的可能存在和作用。这 候选基因的拟议生化活性作为蛋白 将评估酪氨酸磷酸酶。此外， 关于基因的提议活性和/或定位的突变 产品将被解决。最后，信号通路是 候选基因可能会在研究中发挥作用。这种组合 功能和分子方法将证明功能 候选TS基因的活动并开始研究其 作用机制。