Several lines of evidence indicate that aberrant control of protein translation contributes to neoplastic transformation. The signaling pathways that regulate the translational machinery are abnormally active in many human cancers and are causally related to tumor formation in mouse models. Indeed, elevated expression of elF4E can lead to transformation in cultured cells and transgenic mice, and combined Ras and Akt pathways regulate the efficiency by which mRNAs encoding oncogenic proteins are recruited to polysomes. In this grant we will use combinations of germline modification and somatic cell gene transfer modeling strategies to investigate the ability for alterations in the translational efficiencies of existing mRNAs to cause or contribute to tumor formation. We will compare and contrast the requirements of translational control in two tumor types, glioblastoma and prostate cancer, that show critical dependence on signaling through the mTOR and MAPK pathways. To this end, we have developed and will use novel mechanisms of tumor detection in mice. In addition, we will use proteomic strategies to identify how specific protein binding partners of translational control protein and mRNA components are regulated by the signaling activities that cause these cancer types. Briefly, our aims are to: i) examine in Pten mutants the role of Tscl/Tsc2, mTOR, S6K1/S6K2, 4E-BPs and elF4s in tumorigenesis; ii) asses the relevance of deregulated protein translational control in PI-3K and Ras cooperative oncogenesis; iii) determine the role of RheB in oncogenesis; iv) study the role of mTOR in ontogenesis and tumorigenesis; v) characterize the role of S6 kinases in ontogenesis and tumorigenesis; vi) determine the role of 4E-BPs in tumor suppression; vii) study the role of elF4s and their phosphorylation in tumor development and progression; and viii) determine the status of components of the protein translation regulatory network in human cancer.
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