The role of specific PP2A complexes in human cell transformation

描述（由申请人提供）：尽管激酶癌基因是癌症发展的良好特征驱动因素，但对磷酸酶在转化中的作用知之甚少。丝氨酸-苏氨酸蛋白磷酸酶2A（PP 2A）参与调节许多信号传导途径，并可作为肿瘤抑制剂发挥作用。PP 2A是一种异源三聚体蛋白复合物，三个亚基中的每一个都存在几种同种型，产生了一个调节特定生理功能的相关酶的多样化家族。PP 2A异源三聚体的多样性使以前建立特定PP 2A亚基的细胞功能的努力变得复杂。我建议采取三层的方法对PP 2A复合物在癌症进展中的系统表征。使用功能丧失实验，我计划评估特定PP 2A复合物在人类细胞转化中的贡献。通过使用基因组规模的方法，我将确定特定的PP 2A调节亚基在人类癌症中的改变。然后，我将重点破译特定PP 2A复合物在肿瘤抑制中的分子作用，通过定向蛋白质组学方法与细胞转化试验。 公共卫生相关性：这些研究代表了识别可能在癌症治疗中具有诊断和治疗潜力的新靶点的主要步骤。

DESCRIPTION (provided by applicant): Although kinase oncogenes are well-characterized drivers of cancer development, much less is known regarding the role of phosphatases in transformation. The serine-threonine protein phosphatase 2A (PP2A) is implicated in the regulation of numerous signaling pathways and may function as a tumor suppressor. PP2A is a heterotrimeric protein complex, and several isoforms exist for each of the three subunits, creating a diverse family of related enzymes that regulate specific physiological functions. The diversity of PP2A heterotrimers has complicated previous efforts to establish the cellular function of specific PP2A subunits. I propose to take a three-tiered approach toward a systematic characterization of PP2A complexes in cancer progression. Using loss of function experiments I plan to assess the contribution of particular PP2A complexes in human cell transformation. By using genome scale approaches, I will determine alterations of particular PP2A regulatory subunits in human cancers. I will then focus on deciphering the molecular roles of specific PP2A complexes in tumor suppression through a directed proteomics approach together with cell transformation assays. Public Health Relevance: These studies represent primary steps toward the identification of new targets that may have diagnostic and therapeutic potential in the treatment of cancer.