Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 73
Met acts on Mdm2 through mTOR to signal cell survival in vivo
Anice Moumen1, Almudena Porras2, Armand Tasmadjian1, Rosanna Dono1 and Flavio
Maina1
1IBDML, Campus de Luminy-Case 907, 13288 Marseille Cedex 09, France - 2Dpto.
Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense,
Ciudad Universitaria, 28040 Madrid, Spain.
E-mail: maina@ibdm.univ-mrs.fr
Coordination of cell death and survival is crucial during embryogenesis and adulthood and
alterations to this balance can result in degeneration or cancer. Growth factor receptors such
as Met can activate phosphatidyl-inositol-3’ kinase (PI3K), a major intracellular mediator of
growth and survival. PI3K can antagonise p53-triggered cell death but the underlying
mechanisms are not fully understood. Using genetic and pharmacological approaches, we
demonstrated that PI3K acts through mTOR to regulate p53 activity both in vitro and in vivo.
mTOR inhibits p53 by promoting translation of Mdm2, the negative regulator of p53.
Increased Mdm2 protein levels require the mTOR effector p70s6k/S6 ribosomal protein.
Unexpectedly, although it is required for Mdm2 nuclear translocation, Akt is dispensable for
Met-triggered mTOR activation and Mdm2 up-regulation. Inhibition of mTOR is sufficient to
block cell survival induced by HGF/Met in vitro, to down-regulate Mdm2 protein levels and
to induce p53-dependent apoptosis in vivo. Our studies identify a novel mechanism for cell
survival, involving translational regulation of Mdm2 by mTOR, thus reinforcing mTOR as a
potential drug target in cancer.
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