Interactions of the SV40 Small t Antigen and PP2A in Human Cell Transformation

对转化啮齿动物和人类细胞的DNA肿瘤病毒的研究，使人们对 导致恶性状态的分子事件。特别是对病毒癌蛋白的研究 猴病毒40早期区域（SV40 ER）指定的宿主细胞通路， 扰动在哺乳动物细胞的转化中起重要作用。在过去的几年里，我们 已经集中于SV40小T抗原（SV40ST）在人类细胞转化中的作用。在过去 我们已经证实，SV40ST和PP2A之间的相互作用直接有助于 人类细胞转化此外，我们还发现，通过SV 40ST变换对PP2A的扰动 人细胞中以类似于PP2A亚基的癌症相关突变诱导的方式。这些 观察确定PP2A作为人类癌症的肿瘤抑制因子，并表明更深层次的 了解SV40ST干扰PP2A功能的机制将提供更多的见解 肿瘤的发生和维持为了进一步了解PP2A在细胞中的作用， 转化，我们建议结合联合收割机遗传，生物化学和细胞生物学的方法来表征 参与细胞转化的PP2A复合物，以确定RalA在癌症发展中的作用 阐明SV40ST和PP2A干扰人细胞转化的分子途径。 研究PP2A在癌症发展中的调节和功能不仅可以增强我们的研究， 这一肿瘤抑制家族的机制的理解，但也将提供新的见解， 帮助编程恶性状态的途径。此外，这些研究将为以下方面提供基础： 针对这些途径的治疗策略。

The study of DNA tumor viruses that transform rodent and human cells has led to a greater understanding of the molecular events that program the malignant state. In particular, investigation of the viral oncoproteins specified by the Simian Virus 40 Early Region (SV40 ER) has revealed host cell pathways, whose perturbation play an essential role in the transformation of mammalian cells. Over the last several years, we have focused on the role of the SV40 small t antigen (SV40ST) in human cell transformation. During the last funding period, we have confirmed that the interaction between SV40ST and PP2A contributes directly to human cell transformation. In addition, we have found that the perturbation of PP2A by SV40ST transforms human cells in a manner similar to that induced by cancer-associated mutations of PP2A subunits. These observations identify PP2A as a tumor suppressor in human cancers and suggest that a deeper understanding of the mechanisms by which SV40ST perturbs PP2A function will provide additional insights into tumor initiation and maintenance. In order to understand further the role(s) of PP2A in cell transformation, we propose to combine genetic, biochemical and cell biological approaches to characterize the PP2A complexes involved in cell transformation, to identify the role(s) of RalA in cancer development and to elucidate the molecular pathways perturbed by SV40ST and PP2A in human cell transformation. Investigating the regulation and function of PP2A in cancer development will not only enhance our mechanistic understanding of this tumor suppressor family but will also provide new insights into the pathways that help program the malignant state. In addition, these studies will provide a foundation for strategies to target these pathways therapeutically.