p53-dependent translational control of senescence and transformation via 4E-BPs.
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.
Petroulakis
Emmanuel
E
Department of Biochemistry & Goodman Cancer Center, McGill University, Montreal, Quebec, H3G 1Y6, Canada.
Parsyan
Armen
A
Dowling
Ryan J O
RJ
LeBacquer
Olivier
O
Martineau
Yvan
Y
Bidinosti
Michael
M
Larsson
Ola
O
Alain
Tommy
T
Rong
Liwei
L
Mamane
Yaël
Y
Paquet
Marilene
M
Furic
Luc
L
Topisirovic
Ivan
I
Shahbazian
David
D
Livingstone
Mark
M
Costa-Mattioli
Mauro
M
Teodoro
Jose G
JG
Sonenberg
Nahum
N
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
D039561:Eukaryotic Initiation Factor-4E; D016159:Tumor Suppressor Protein p53