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.

（改编自研究者摘要） 肿瘤细胞的致瘤能力涉及遗传 导致癌基因激活和癌基因丢失的改变 肿瘤抑制基因的功能。该项目的目标是 鉴定、确认和表征肿瘤抑制（TS）基因定位 与染色体10的长臂（10 q23 -24）密切相关 胶质瘤进展为高级别多形性胶质母细胞瘤（GMB）。一 最近，一个强有力的候选抑制基因被发现存在于 关键区域。删除大段或整个副本， 染色体10代表了一个非常常见的（-90%）分子 GBM和其他几种癌症的改变。该研究的假设 提出了10号染色体上肿瘤抑制基因功能的丧失 直接导致这些癌症的发展。候选人TS 在关键区域克隆的基因似乎编码一种新的蛋白质 酪氨酸磷酸酶（PTH 4），暗示了一个潜在的作用， 候选TS基因在细胞信号转导中的作用。他们以前使用过一种 微细胞介导的染色体转移的功能方法， 证明10 q上TS基因的存在和生物学功能 参与神经胶质瘤的发生。为了进一步定义TS位点， 采用了三种独立的方法来定义临界区域， 包括胶质瘤细胞中纯合缺失的鉴定。所有 三种方法及等位基因缺失分析 癌症将注意力集中在一个位点上。一个基因现在 从这个关键区域克隆并跨越纯合缺失。 培养的胶质瘤和前列腺细胞中的基因突变， 在几个人肿瘤标本中观察到了改变。基序 分析表明该基因产物是一种新的PTD 3。这项建议是 针对候选TS基因的表征。肿瘤 候选基因的抑制活性将通过检测 将候选基因的各种构建体导入神经胶质瘤细胞。突变 以及生殖系突变的可能存在和影响。的 候选基因作为蛋白质的拟定生化活性 将评估酪氨酸磷酸酶。此外， 对基因的拟定活性和/或定位的突变 产品将得到解决。最后，信号通路， 候选TS基因可能发挥的作用将被检查。的这种组合 功能和分子方法将证明功能 候选TS基因的活性，并开始对其进行研究 作用机制。