Viral Oncoprotein Inhibition of Quiescence

小DNA肿瘤病毒SV40的急性感染可以驱使静止的哺乳动物细胞进入细胞周期。 至少有一部分工作是由SV40 LT完成的，SV40 LT是两种病毒癌蛋白之一。其余的都是 ST在这一过程中的作用取决于它的干扰能力， 蛋白磷酸酶PP2A的功能，PP2A是已知的人类肿瘤抑制基因的产物。 出乎意料的是，静止控制的SV40 ST扰动的至少部分机制是 针对发生在G2（或G2/M）中的事件。G2期间ST靶向的过程是PP2A依赖性的 并且在下一个G1期开始的有丝分裂原剥夺后细胞必须保持完整才能静止。也 涉及的是p130/E2F4/DREAM复合物，其完整性依赖于PP2A。 被证明在维持静止状态中起作用。以G2为中心的PP2A是否起作用和/或 在细胞周期期间的另一时间运行的PP2A功能与该复合体通信以许可 静止不清。拟议研究的主旨旨在了解1）如何在分子水平上 2）其扰动是否有助于SV40 ST依赖 肿瘤转化和肿瘤发生，以及3）如果是这种情况，其扰动是如何产生的 这些影响。

Acute infection by the small DNA tumor virus, SV40, can drive quiescent mammalian cells into the cell cycle. At least part of this work is performed by SV40 LT, one of the two viral oncoproteins. The rest is performed by the other oncoprotein, SV40 ST. The role of ST in this process depends upon its ability to interfere with the function of the protein phosphatase, PP2A, the product of a known human.tumor suppressing gene. Unexpectedly, at least part of the mechanism underlying SV40 ST perturbation of quiescence control is directed at events that occur in G2 (or G2/M). The process targeted by ST during G2 is PP2A- dependent and must be intact for cells to quiesce following mitogen deprivation initiated during the next G1 phase. Also involved is the p130/E2F4/DREAM complex, the integrity of which is PP2A dependent, This complex has been shown to operate in the maintenance of quiescence. Whether G2-centered PP2A function and/or PP2A function operating at another time(s) during the cell cycle communicates with this complex to license quiescence is unclear. The thrust of the proposed research is aimed at understanding 1) how, in molecular terms, the G2 quiescence control process operates, 2) whether its perturbation contributes to SV40 STdependent neoplastic transformation and tumorigenesis and 3), if this is the case, how its perturbation elicits these effects.