PTEN is a tumor suppressor that negatively regulates the phosphoinositide 3-kinase (PI3K) signaling pathway, a central mediator of signal transduction for growth, proliferation and cell survival. PTEN is inactivated by somatic mutation in diverse human tumors including glioblastoma, endometrial carcinoma, and prostate carcinoma. Germline mutations in PTEN result in a number of phenotypic abnormalities with variable penetrance including macrocephaly, hamartomas in multiple tissues, cancer predisposition, and neurological abnormalities. Thus PTEN inactivation has consequences in multiple organ systems, and causes tumorigenesis and developmental abnormalities in the nervous system. The goal of our work is to determine Pten function in the regulation of normal and neoplastic growth in the brain. Towards this goal, we used cre -lox technology to selectively inactivate Pten in granule neurons of the cerebellum and dentate gyrus in mouse. Our preliminary data showed that Pten deficiency results in a dramatic loss of neuronal size regulation in adult mice, and abnormalities in cell migration. Unexpectedly, we did not observe differences in neuronal proliferation and survival despite a defined role of the PI3K pathway in these processes in granule cells. We hypothesize that Pten is critical for the appropriate control of downstream effectors required for cell growth control and tumor suppression. We propose studies to determine the contribution of the downstream effectors Akt, mTor and S6k to the Pten-mediated regulation of neuronal size. We will also identify other gene targets that are involved in growth regulation. Finally, we will determine the effects of Pten deficiency on cell growth, proliferation, survival, and tumorigenic potential in astrocytes, the cell background that gives rise to PTEN-deficient glioblastomas. We will determine if the same signaling pathways that contribute to aberrant regulation of cell size in post-mitotic neurons are critical to Pten function in normal and neoplastic growth in astrocytes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-4 (01))
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Tagle, Danilo A
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St. Jude Children's Research Hospital
United States
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