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 对恶性状态进行编程的分子事件。特别是病毒癌蛋白的研究 由猿猴病毒40早期区(SV40 ER)指定，揭示了宿主细胞途径，其 扰动在哺乳动物细胞的转化中起着至关重要的作用。在过去的几年里，我们 都集中在SV40小T抗原(SV40ST)在人类细胞转化中的作用。在过去的几年里 在资助期内，我们已经确认SV40ST和PP2A之间的相互作用直接有助于 人类细胞的转化。此外，我们还发现，SV40ST对PP2A的扰动会转化为 以与癌症相关的PP2A亚单位突变所诱导的方式相似的方式诱导人类细胞。这些 观察发现，PP2A是人类癌症中的一种肿瘤抑制因子，并提示更深层次的 理解SV40ST干扰PP2A功能的机制将提供更多的见解 肿瘤的启动和维持。为了进一步了解PP2A在细胞中的作用(S) 转化，我们建议结合遗传学、生化和细胞生物学的方法来表征 参与细胞转化的PP2A复合体，以确定Rala在肿瘤发展中的作用(S) 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将增强我们的 从机制上理解这一抑癌基因家族，也将为我们提供新的见解 帮助设定恶性状态的途径。此外，这些研究将为 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.