COBRE P1: MOLECULAR MECHANISMS OF AURORA KINASE A DYSFUNCTION IN LUNG CANCER

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 八年前，极光激酶A被归类为癌基因。这种蛋白在许多形式的癌症中都有高水平的表达，包括胃癌、结直肠癌、乳腺癌、食道癌和肺癌。事实上，多达86%的肺癌表现出Aurora A的不适当表达。仅仅过度表达这种蛋白就可以将某些正常细胞转化为肿瘤。重要的是，由高Aurora A激酶活性产生的肿瘤显示出对包括紫杉醇在内的靶向微管形成的药物的耐药性增加。事实上，目前正在进行极光激酶活性的小分子抑制剂治疗癌症的临床试验。然而，人们对该激酶的分子靶点知之甚少。这种转变是如何发生的？Aurora A正常功能以外的蛋白质是否参与了这一过程？目前这项提案的目标是利用高效质谱学、蛋白质组学定量策略和选择性磷酸肽富集法的组合能力，在蛋白质组范围内综合表征Aurora A激酶的底物。这些信息是我们可以开始了解不受调控的Aurora A激酶活性如何导致肺癌以及如何治疗它的关键基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Eight years ago, Aurora kinase A was classified as an oncogene. This protein has been found at high levels in many forms of cancer, including gastric, colorectal, breast, esophageal and lung cancers  indeed, as many as 86% of lung cancers exhibit inappropriate expression of Aurora A. Simply overexpressing this kinase can transform certain normal cells into tumors. Importantly, tumors generated by high Aurora A kinase activity demonstrate increased resistance to drugs that target microtubule formation, including Taxol. In fact, clinical trials are currently underway for small molecule inhibitors of Aurora kinase activity in treating cancer. However, very little is known about the molecular targets of this kinase. How does this transformation occur? Are proteins outside of the normal function of Aurora A involved in this process? It is the goal of the current proposal to tap into the combined power of high performance mass spectrometry, quantitative strategies in proteomics, and selective phosphopeptide enrichment methods to comprehensively characterize substrates of Aurora A kinase, on a proteome-wide scale. This information is a critical foundation from which we can begin to understand how unregulated Aurora A kinase activity causes lung cancer, and how to treat it.