Browsing by Subject "Translational Control"

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    Translational control of cancer: an exploration of eIF4E and its role in cellular oncogenic transformation.
    (2009-04) Underwood II, Jon Michael
    Cancer is currently the 2nd leading cause of death in the U.S., responsible for approximately one quarter of the annual death rate. While cancer is genetically diverse, we suspect there may be common components of the cellular machinery where oncogenic signals converge, and that these critical regulatory nodes may represent molecular targets for new therapies. My approach derives from recent work on human breast and lung carcinoma, and murine models of lymphoid malignancies; which identify the cap-dependent protein synthesis machinery as a critical point of convergence and amplification of oncogenic signals emanating from the Ras/PI3K/Akt cascade. The rate limiting step in protein synthesis is initiation, mediated by the trimeric protein eukaryotic initiation factor 4F (eIF4F). The limiting component of eIF4F is the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Over expression of eIF4E transforms immortalized rodent fibroblasts and confers primary human cells with several cancer-related functions including decreased growth factor requirement for proliferation and survival, colony formation and anchorage independence. However, until very recently all experiments examining the oncogenic potential of eIF4E have involved constitutive over expression in stably transfected cell lines; leaving uncertain precisely which oncogenic functions could be ascribed directly to eIF4E, and which relate to its ability to suppress apoptosis - thus creating a permissive environment for subsequent oncogenic mutations. I have developed a high fidelity eIF4E inducible system which allows me to abruptly activate eIF4E over expression. With this system I am able to establish a direct connection between eIF4E induction and autonomous cell proliferation. I have also been able to specify the cell cycle kinetics which occurs after eIF4E induction, including the ability of eIF4E to bypass growth factor initiation on the canonical proliferative pathway. The growth factor bypass properties of eIF4E are due to its ability to translationally activate cyclin D1, an occurrence I report for the first time. I also demonstrate the potential of pharmacological intervention targeting hyperactive translational activity. With the use of small molecular compounds which antagonize translation initiation, I demonstrate the ability to reverse eIF4E triggered proliferation in the eIF4E inducible system and the selective elimination of cancer cells with minimal toxicity in normal cells. This study has lead to a better understanding of how cap-dependent translation regulates cell proliferation and advanced the novel concept for cancer biology and therapeutics focused on translational control.