Translation initiation: a critical signalling node in cancer.
Mammalian target of rapamycin (mTOR) is a master regulator of translation initiation that controls the recruitment of ribosomes to mRNA templates in response to intracellular and extracellular cues. Evidence suggests that mTOR and its direct downstream targets, S6K and eIF4E/4E-BP, play significant roles in oncogenesis, and that inhibiting this pathway holds promise as an anti-proliferative approach. Recent genome-wide analyses of mutations in human cancers indicate that transformed cells activate a handful of processes and signalling pathways that are major contributors to their phenotype. Here we review the current literature implicating mTOR and translation initiation downstream of many of these various signalling pathways and processes usurped in human cancers. This review highlights the widespread activation of mTOR/eIF4E following acquisition of oncogenic lesions and its implication in promoting the transformation phenotype and indicates that targeting the control of translation initiation makes logical sense as a broad-acting therapeutic approach.
Robert
Francis
F
Department of Biochemistry and Goodman cancer centre, McGill University, McIntyre Medical Sciences Building, Room 810, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada.
Pelletier
Jerry
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases