title: p53-dependent translational control of senescence and transformation via 4E-BPs.
abstract: eIF4E, the mRNA 5' cap-binding translation initiation factor, is overexpressed in numerous cancers and is implicated in mechanisms underlying oncogenesis and senescence. 4E-BPs (eIF4E-binding proteins) inhibit eIF4E activity, and thereby act as suppressors of eIF4E-dependent pathways. Here, we show that tumorigenesis is increased in p53 knockout mice that lack 4E-BP1 and 4E-BP2. However, primary fibroblasts lacking 4E-BPs, but expressing p53, undergo premature senescence and resist oncogene-driven transformation. Thus, the p53 status governs 4E-BP-dependent senescence and transformation. Intriguingly, the 4E-BPs engage in senescence via translational control of the p53-stabilizing protein, Gas2. Our data demonstrate a role for 4E-BPs in senescence and tumorigenesis and highlight a p53-mediated mechanism of senescence through a 4E-BP-dependent pathway.
authors.affiliation: Department of Biochemistry & Goodman Cancer Center, McGill University, Montreal, Quebec, H3G 1Y6, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Petroulakis
authors.forename: Armen
authors.initials: A
authors.lastname: Parsyan
authors.forename: Ryan J O
authors.initials: RJ
authors.lastname: Dowling
authors.forename: Olivier
authors.initials: O
authors.lastname: LeBacquer
authors.forename: Yvan
authors.initials: Y
authors.lastname: Martineau
authors.forename: Michael
authors.initials: M
authors.lastname: Bidinosti
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.forename: Liwei
authors.initials: L
authors.lastname: Rong
authors.forename: Yaël
authors.initials: Y
authors.lastname: Mamane
authors.forename: Marilene
authors.initials: M
authors.lastname: Paquet
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.forename: David
authors.initials: D
authors.lastname: Shahbazian
authors.forename: Mark
authors.initials: M
authors.lastname: Livingstone
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
authors.forename: Jose G
authors.initials: JG
authors.lastname: Teodoro
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D016159:Tumor Suppressor Protein p53