Translational Control of Cancer

University Of Minnesota, Minneapolis MN

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Cancer is currently the 2nd leading cause of death in the U.S., responsible for approximately one quarter of the annual death rate. 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 carcinoma and murine lymphoid malignancies, which identifies the cap-dependent protein synthesis machinery, specifically eukaryotic initiation factor 4E (elF4E), as a critical point of convergence and amplification of oncogenic signals. I intend to define cell cycle kinetics after induction of elF4E expression in quiescent fibroblasts harboring a mifipristone inducible elF4E construct, and determine which transcripts encoding cell cycle regulators are recruited to polyribosomes when ectopic elF4E triggers cell cycle entry. Finally I plan on using novel nucleoside-based elF4E antagonists to define the relationships among elF4E activity, cap-dependent protein synthesis, recruitment of transcripts encoding specific cell cycle regulators and the kinetics of cell cycle entry. The long term goal of targeting the machinery involved in cap-dependent translation is to provide a novel avenue of drug development which reverses cancer and thereby improves human health. [unreadable] [unreadable] [unreadable]