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.

Public Health Relevance

The two cellular proteins, Akt and protein phosphatase 2A, are known to be important for a variety of human tumors. Cell survival is a key issue in cancer. This work will explain how the two proteins can be switched from promoting cell survival to causing cell death.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Dana-Farber Cancer Institute
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