Novel human oncogene STK15/BTAK/Aurora 2

描述：(申请者提供)我们克隆了一种新的人类激酶 编码基因(STKI5/BTAKaurora2)，位于染色体20q13上，即 在许多不同类型的人类肿瘤细胞中扩增/过表达(Sen等人， 癌基因14：2195-2200；周、钟、郭、格雷、布林克利和自然参议员 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、非整倍体与致瘤转化 在哺乳动物细胞中。在大约50个细胞中检测到STK15的过度表达 未选择的原发结肠肿瘤的百分比和基因扩增在 约12%的未经选择的原发乳腺肿瘤。超越这一切的所有目标 该项目包括阐明参与维持的STK15途径 正常细胞和癌细胞的基因组稳定性和非整倍体诱导 分别进行了分析。我们还建议评估其致病遗传学意义。 STK15蛋白及其相互作用蛋白在人结肠癌细胞中的表达这个 这个项目的具体目标是：1.确定STK15的相互作用 激酶及其潜在的调节蛋白和效应蛋白通过G2-M 细胞分裂周期的阶段。这一结果将有助于理解 这些相互作用在细胞的G2-M-后期进程中起作用。 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，以及b)与相互作用的蛋白质结合。结果将是 有助于阐明调节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细胞周期调控中的作用。 增殖过程中中心体功能和染色体稳定性的调节 通过与合适的野生型共转染实验在体内的细胞 和突变的表达结构。这些研究的结果预计将 阐明STK15参与维持基因组稳定性的途径 以及激活导致细胞转化的变化 基因的异常高表达。 4.确定STK15激酶及其相互作用的表达谱 不同组织学分级和分期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 STK15通路在肺癌诊断和预后中的意义

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.