The Role of Polyoma Small T in Regulating Cell Survival

肿瘤发展和生长的基本重要机制已被反复研究。 是通过研究多瘤病毒发现的酪氨酸激酶活性、磷酸肌醇3-激酶（PI 3 K）活性 和抑癌基因p53都在那里被发现。我们最近发现一种病毒 癌基因，小T（PyST），可以通过引起或阻止许多不同细胞的存活来调节 凋亡为了在杀死和促进存活之间切换，PyST使用重要的细胞磷酸酶 PP2A.将确定这种生死决定所需的许多PP 2A物种中的哪一种。 PyST/PP 2A作用的一个关键靶标是细胞激酶Akt。由于Akt通常被视为 促存活蛋白，它可以是凋亡刺激的观察是相当具有挑衅性的。PyST/PP 2A 调节其T308和S473调节位点上的Akt磷酸化。其结果是， Akt底物的磷酸化。Akt在一般情况下的作用和不对称磷酸化在 具体将予以确认。将检查Akt底物在细胞杀伤中的作用。很可能 除了Akt之外的其它靶标对于PyST杀伤也是重要的。将进行无偏倚筛选， 找出其他相关的途径。最有可能的直接目标是PyST结合的目标， 与PP 2A一起使用。新的PyST结合蛋白，可能需要细胞杀伤将被确定。 鼠多瘤病毒的一个优点是可以在小鼠中测试信号转导假说。我们 已经发现了一个技巧，可以让我们比较有PyST的病毒和没有PyST的病毒。是否 PyST是病毒生长所必需的，更重要的是，它如何有助于多瘤肿瘤的特征将被研究。 测试. PyST/PP 2A在某些组织中可以作为肿瘤抑制因子发挥作用的假设将是 用肝脏作为模型进行检查。这项工作的结果将是更充分地了解PP 2A和 Akt参与生与死的决定。它应该阐明新的信号转导机制。在 将来，我们在这里获得的知识可能使我们有选择地减少癌细胞的存活。

Mechanisms of fundamental importance for tumor development and growth have been repeatedly uncovered by studying polyomaviruses. Tyrosine kinase activity, phosphoinositide 3-kinase (PI3K) activity and the tumor suppressor p53 were all discovered there. We have recently discovered that one viral oncogene, small T (PyST), can regulate survival in many different cells by causing or by preventing apoptosis. To switch between killing and promoting survival PyST uses the important cellular phosphatase PP2A. Which of the many PP2A species required for this life and death determination will be determined. One key target of PyST/PP2A action is the cellular kinase Akt. Since Akt is generally viewed as a pro-survival protein, the observation that it can be an apoptotic stimulus is quite provocative. PyST/PP2A modulates Akt phosphorylation on its T308 and S473 regulatory sites. The result is a differential alteration in the phosphorylation of Akt substrates. The role for Akt in general and for the asymmetric phosphorylation in particular will be confirmed. Akt substrates will be examined for their role in cell killing. It is likely that additional targets besides Akt are important for PyST killing. Non-biased screens will be performed to identify other pathways that are involved. The most likely direct targets would be ones that PyST binds and brings together with PP2A. New PyST binding proteins that might be required for cell killing will be identified. An advantage of murine polyomavirus is that signal transduction hypotheses can be tested in mice. We have uncovered a trick that will allow us to compare a virus that has PyST to one that does not. Whether PyST is required for virus growth and more importantly how it contributes to the polyoma tumor profile will be tested. The hypothesis that PyST/PP2A can function as a tumor suppressor in some tissues will be examined using liver as a model. The outcome of this work will be a fuller understanding of how PP2A and Akt participate in life and death decisions. It should illuminate new signal transduction mechanisms. In the future the knowledge gained here might allow us to decrease the survival of cancer cells selectively.