Mechanisms of Akt-dependent sensitivity to rapamycin

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DESCRIPTION (provided by applicant): The long range goal of the proposal is to investigate the mechanism of cap-independent translation of the c- myc protein with the assumption that its cellular function is a key determinant of tumor cell responses, especially for CNS malignancies. More specifically, the proposal will elucidate how hnRNP A1 (A1) functions as a trans-acting protein that binds to the internal ribosome entry site (IRES) in the 5' UTR of the c-myc transcript, thus facilitating IRES-dependent translation of myc. Furthermore, it will focus on the ability of Akt and MAPK cascades to regulate this A1 translation-promoting activity, testing effects on the IRES-annealing activity of A1, effects on IRES-ribosome binding and effects on A1/IRES subcellular localization. Glioma cell lines, primary tumor cells and xenograft models will be used to exploit the insight gained on A1/myc IRES regulatory controls to understand mechanisms of glioma cell resistance whe treatment with mTOR inhibitors is attempted. PUBLIC HEALTH RELEVANCE: The project details the mechanisms by which glioma tumor cells become resistant to promising new therapeutic agents called mTOR inhibitors. The mechanisms of cell intrinsic resistance to these compounds will be investigated, as well as, the pre-clinical evaluation of combination targeted therapies in glioma in vitro and in vivo models.