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Aurora-A/BTAK/STK15 Oncoprotein in Mitotic Spindle Assembly and Checkpoint Respon

有丝分裂纺锤体组装和检查点反应中的 Aurora-A/BTAK/STK15 癌蛋白

基本信息

批准号：
8304400
负责人：
Subrata Sen
金额：
$ 26.82万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-26 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304400
关键词：
Binding CENP-E protein Cancer Patient Carcinoma Cell Death Cell Survival Cells Centrosome Chromatin Chromosomal Instability Chromosome Segregation Chromosomes Clinical Trials Complex Development FHA Domain Genes Genetic Goals Health Human Human Characteristics In Situ In Vitro Kinetochores Knockout Mice Laboratories Malignant Neoplasms Mammalian Cell Maps Mediating Microtubules Mitochondrial Membrane Protein Mitosis Mitotic Mitotic Checkpoint Mitotic Chromosome Mitotic spindle Molecular Profiling Mus Nature Oncogene Proteins Oncogenes Oncogenic Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphorylation Site Phosphotransferases Predisposition Process Proteins Publications RNA RNA Binding RNA-Binding Proteins Recovery Regulation Reporting Role STK6 gene Specimen Tissues Work Xenograft Model aurora kinase aurora-A kinase cancer therapy checkpoint kinase 2 genetic regulatory protein human STK6 protein in vivo inhibitor/antagonist inner centromere protein kinase inhibitor malignant breast neoplasm mouse model mutant novel protein complex protein expression protein function response segregation small molecule treatment response tumor

项目摘要

DESCRIPTION (provided by applicant): Aurora-A/BTAK/STK15 is a critical regulator of mitotic chromosome segregation and a putative oncoprotein capable of inducing chromosomal instability and oncogenic transformation when ectopically over expressed in mammalian cells in vitro and in vivo. A significant correlation has been reported between elevated expression of the protein and chromosomal instability in many different types of human cancers and several clinical trials of small molecule Aurora kinase inhibitors for cancer therapy are currently underway. Our recent work on molecular interactions of Aurora-A in human cells and the development of a knockout mouse model have provided compelling evidence in favor of novel functional roles of Aurora-A in mitotic spindle assembly and checkpoint as well as cell survival pathways. The results have revealed that Aurora-A is the key regulator of both kinetochore/chromatin and centrosome associated microtubule formation processes contributing to bipolar spindle assembly and that loss of Aurora-A function leads to cell death following mitotic disarray. This application proposes to investigate the functional significance of novel Aurora-A protein interactions, recently detected in our laboratory, in the regulation of mitotic spindle assembly, mitotic checkpoint and cell survival/cell death response pathways in human cells. Additionally, expression patterns of these Aurora-A interacting proteins will be correlated with response to therapy and overall survival in human breast cancer patients. The study will have the following specific aims: 1. Investigate the role of Aurora-A in kinetochore/chromatin associated microtubule assembly in reference to its functional interactions with INCENP and the chromosome passenger complex proteins. 2. Investigate the role of novel centrosome/spindle pole associated Aurora-A interactions with Translin, EF11 and Hsp90 in spindle assembly. 3. Investigate the role of Aurora-A-CENP-E interaction on spindle assembly checkpoint pathway. 4. Investigate the role of two novel Aurora-A interacting proteins, the Chk2 kinase and the mitochondrial membrane protein MTP18 in the survival of cells and in the activation of mitotic cell death response in the absence or presence of spindle damaging drugs. 5. Investigate the expression status of the novel Aurora-A interacting proteins in human breast cancer tissue specimens with in situ and invasive carcinoma. The results are expected to provide a comprehensive picture of Aurora-A regulated pathways in mitotic progression including chromosome alignment, segregation, checkpoint and cell survival/cell death response in human cells as well as evaluate the significance of Aurora-A interacting proteins in response to therapy and over all survival of human breast cancer patients. PUBLIC HEALTH RELEVANCE: This project proposes to: 1. Investigate the significance of novel kinetochore and centrosome associated Aurora-A functional interactions in kinetochore and centrosome associated mitotic spindle assembly. 2. Investigate the significance of novel Aurora-A functional interactions with Cenp- E, Chk2 and MTP18 in checkpoint and cell survival/cell death response in human cells exposed to spindle damaging agents and correlate the expression profiles of these proteins with response to therapy in human breast cancer patients.

描述（由申请方提供）：Aurora-A/BTAK/STK 15是有丝分裂染色体分离的关键调节因子，是一种推定的癌蛋白，当在体外和体内哺乳动物细胞中异位过表达时，能够诱导染色体不稳定性和致癌转化。已经报道了在许多不同类型的人类癌症中蛋白质的表达升高与染色体不稳定性之间的显著相关性，并且目前正在进行用于癌症治疗的小分子极光激酶抑制剂的几项临床试验。我们最近对Aurora-A在人类细胞中的分子相互作用的研究和敲除小鼠模型的开发提供了令人信服的证据，支持Aurora-A在有丝分裂纺锤体组装和检查点以及细胞存活途径中的新功能作用。结果表明，Aurora-A是着丝粒/染色质和中心体相关微管形成过程的关键调节因子，有助于双极纺锤体组装，并且Aurora-A功能的丧失导致有丝分裂混乱后的细胞死亡。本申请旨在研究我们实验室最近检测到的新型Aurora-A蛋白相互作用在人类细胞有丝分裂纺锤体组装、有丝分裂检查点和细胞存活/细胞死亡反应途径调节中的功能意义。此外，这些Aurora-A相互作用蛋白的表达模式将与人类乳腺癌患者对治疗的反应和总生存率相关。本研究的具体目标如下：1.研究Aurora-A在着丝粒/染色质相关微管组装中的作用，参考其与INCENP和染色体乘客复合物蛋白的功能相互作用。2.研究新型中心体/纺锤体极相关Aurora-A与翻译蛋白、EF 11和Hsp 90相互作用在纺锤体组装中的作用。3.研究Aurora-A-CENP-E相互作用在纺锤体组装检查点通路中的作用。4.研究两种新的Aurora-A相互作用蛋白，Chk 2激酶和线粒体膜蛋白MTP 18在细胞存活和有丝分裂细胞死亡反应的激活中的作用，无论是否存在纺锤体损伤药物。5.研究新的Aurora-A相互作用蛋白在人乳腺癌原位癌和浸润癌组织标本中的表达状态。这些结果预计将提供Aurora-A在有丝分裂进程中调节途径的全面图片，包括人类细胞中的染色体对齐，分离，检查点和细胞存活/细胞死亡反应，以及评估Aurora-A相互作用蛋白在响应治疗和人类乳腺癌患者的所有生存中的意义。公共卫生相关性：本项目建议：1.研究新的动粒和中心体相关的Aurora-A功能相互作用在动粒和中心体相关的有丝分裂纺锤体组装中的意义。2.研究新型Aurora-A与Cenp-E、Chk 2和MTP 18的功能性相互作用在暴露于纺锤体损伤剂的人类细胞中的检查点和细胞存活/细胞死亡应答中的意义，并将这些蛋白质的表达谱与人类乳腺癌患者对治疗的应答相关联。