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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 八年前，极光激酶A被归类为致癌基因。 这种蛋白质在许多癌症中都有很高的水平，包括胃癌、结肠直肠癌、乳腺癌、食道癌和肺癌。  事实上，多达86%肺癌表现出Aurora A的不适当表达。 简单地过度表达这种激酶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表现出对靶向微管形成的药物（包括紫杉醇）的耐药性增加。 事实上，目前正在进行Aurora激酶活性小分子抑制剂治疗癌症的临床试验。然而，对这种激酶的分子靶点知之甚少。 这种转变是如何发生的？ Aurora A正常功能之外的蛋白质是否参与了这一过程？ 这是目前建议的目标，利用高性能质谱，蛋白质组学定量策略和选择性磷酸肽富集方法的组合能力，在蛋白质组范围内全面表征Aurora A激酶的底物。 这些信息是我们开始了解不受调节的Aurora A激酶活性如何导致肺癌以及如何治疗肺癌的关键基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.