p53-dependent translational control of senescence and transformation via 4E-BPs

Emmanuel Petroulakis, Armen Parsyan, Ryan Dowling, Olivier LeBacquer, Yvan Martineau, Michael Bidinosti, Ola Larsson, Tommy Alain, Liwei Rong, Yael Mamane, Marilene Paquet, Luc Furic, Ivan Topisirovic, David Shahbazian, Mark Livingstone, Mauro Costa-Mattioli, Jose Teodoro, Nahum Sonenberg

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84 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)439 - 446
Number of pages8
JournalCancer Cell
Volume16
Issue number5
DOIs
Publication statusPublished - 2009
Externally publishedYes

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