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

• 批准号: 8127846
• 负责人: Subrata Sen
• 金额: $ 26.83万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127846
• 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

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(申请人提供)：Aurora-A/BTAK/STK15是有丝分裂染色体分离的关键调节因子，当在体外和体内的哺乳动物细胞中异位过度表达时，可能会导致染色体不稳定和致癌转化。据报道，在许多不同类型的人类癌症中，该蛋白的高表达与染色体不稳定性之间存在显著的相关性，目前正在进行几项用于癌症治疗的小分子Aurora激酶抑制剂的临床试验。我们最近对Aurora-A在人类细胞中的分子相互作用以及基因敲除小鼠模型的发展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生存途径中的新功能。结果表明，Aurora-A是动粒/染色质和中心体相关微管形成过程的关键调节因子，有助于双极纺锤体的组装，并且Aurora-A功能的丧失会导致有丝分裂紊乱后的细胞死亡。这项应用旨在研究我们实验室最近发现的新的Aurora-A蛋白相互作用在调节人类细胞有丝分裂纺锤体组装、有丝分裂检查点和细胞生存/细胞死亡反应通路中的功能意义。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的治疗反应和总存活率相关。本研究的具体目的如下：1.研究Aurora-A与INCENP和染色体乘客复合体蛋白的功能相互作用，探讨Aurora-A在动粒/染色质相关微管组装中的作用。2.研究新的中心体/纺锤体极相关的Aurora-A与Translin、EF11和Hsp90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Chk2和线粒体膜蛋白MTP18在细胞存活和有丝分裂细胞死亡反应的激活中的作用。5.研究新型Aurora-A相互作用蛋白在人乳腺癌原位癌和浸润性癌组织中的表达情况。这些结果有望全面了解Aurora-A在人类细胞有丝分裂进程中的调控途径，包括染色体配对、分离、检查点和细胞生存/细胞死亡反应，并评估Aurora-A相互作用蛋白在治疗反应和人类乳腺癌患者总体生存中的意义。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极光-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、Chk2和MTP18的功能相互作用在纺锤体损伤剂暴露的人细胞中的检查点和细胞存活/细胞死亡反应中的意义，并将这些蛋白的表达谱与乳腺癌患者的治疗反应相关联。