Novel human oncogene STK15/BTAK/Aurora 2

人类新癌基因 STK15/BTAK/Aurora 2

• 批准号: 6794608
• 负责人: Subrata Sen
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-26 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6794608
• 关键词: aneuploidy; centrosome; colon neoplasms; enzyme activity; enzyme induction /repression; human tissue; neoplasm /cancer genetics; neoplastic growth; oncogenes; posttranslational modifications; protein kinase; protein protein interaction

DESCRIPTION: (provided by applicant) We have cloned a novel human kinase encoding gene (STKI5/BTAKaurora2), harbored on chromosome 20q13 that is amplified/overexpressed in many different human tumor cell types (Sen et al, Oncogene 14:2195-2200; Zhoui Kuang, Zhong, Kuo, Gray, Brinkley and Sen. Nature Genetics 20:189-193, 1998). Over-expression of this gene induces abnormal centrosome duplication/distribution, aneuploidy and tumorigenic transformation in mammalian cells. Over expression of STK1 5 has been detected in about 50 percent of unselected primary colon tumors and gene amplification detected in about 12 percent of unselected primary breast tumors. Over all goals of this project include elucidating the STK1 5 pathway that is involved in maintaining genomic stability and induction of aneuploidy in normal and cancer cells respectively. We also propose to evaluate the patho-genetic significance of STK1 5 protein and STK1 5 interacting proteins in human colon cancer cells. The specific aims of this project are to: 1. Identify the interactions of STK1 5 kinase with its potential regulator and effector proteins through the G2-M phase of the cell division cycle. The results would help understand the role of these interactions in G2-M-Anaphase progression of cells. 2. Investigate amino acid structural requirements and post-translational modifications required for a) STK1 5 sub-cellular localization including targeting to centrosomes, and b) binding to interacting proteins. Results would help elucidate the biochemical mechanisms regulating STK1 5 localization and their functional relevance. 3. Investigate the role of STK1 5 and its interacting proteins in the regulation of centrosome function and chromosomal stability in proliferating cells in vivo through co-transfection experiments with appropriate wild type and mutant expression constructs. The findings of these studies are expected to elucidate the pathway that involves STK1 5 in maintaining genomic stability as well as in activating changes leading to transformation of cells due to abnormally elevated expression of the gene. 4. Determine the expression profiles of STK15 kinase and its interacting proteins in colon cancer specimens of different histological grades and stages with or without chromosomal instability phenotypes. Results would help assess the diagnostic and prognostic significance of STK1 5 pathway in this cancer.

描述：（由申请人提供）我们克隆了一种新型人类激酶 编码基因（STKI5/BTAKaurora2），位于染色体 20q13 上，即 在许多不同的人类肿瘤细胞类型中扩增/过表达（Sen 等人， 癌基因 14：2195-2200； Zhoui Kuang、Zhong、Kuo、Gray、Brinkley 和 Sen. Nature 遗传学 20：189-193，1998）。该基因的过度表达会导致异常 中心体复制/分布、非整倍性和致瘤转化 在哺乳动物细胞中。已在约 50 个细胞中检测到 STK1 5 过度表达 未选择的原发性结肠肿瘤的百分比和检测到的基因扩增 约 12% 的未经选择的原发性乳腺肿瘤。综上所述的所有目标 项目包括阐明参与维持的 STK1 5 通路 正常细胞和癌细胞中的基因组稳定性和非整倍性的诱导 分别。我们还建议评估其病理遗传学意义 人结肠癌细胞中的 STK1 5 蛋白和 STK1 5 相互作用蛋白。这 该项目的具体目标是： 1. 确定 STK1 5 的相互作用 激酶及其通过 G2-M 的潜在调节蛋白和效应蛋白 细胞分裂周期的阶段。结果将有助于理解 这些相互作用在细胞的 G2-M-后期进展中。 2. 研究氨基酸结构要求和翻译后 a) STK1 5 亚细胞定位所需的修改包括 靶向中心体，b) 与相互作用的蛋白质结合。结果会 帮助阐明调节 STK1 5 定位的生化机制和 它们的功能相关性。 3. 研究 STK1 5 及其相互作用蛋白在 增殖过程中中心体功能和染色体稳定性的调节 通过与适当野生型的共转染实验体内细胞 和突变体表达构建体。这些研究的结果预计将 阐明涉及 STK1 5 维持基因组稳定性的途径 以及激活导致细胞转化的变化 该基因的表达异常升高。 4. 确定 STK15 激酶及其相互作用的表达谱 不同组织学分级和阶段的结肠癌标本中的蛋白质 有或没有染色体不稳定表型。结果将有助于评估 STK1 5 通路在这种癌症中的诊断和预后意义。