Met acts on Mdm2 via mTOR to signal cell survival during development.
Coordination of cell death and survival is crucial during embryogenesis and adulthood, and alteration of 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 then antagonize p53-triggered cell death, but the underlying mechanisms are not fully understood. We used genetic and pharmacological approaches to uncover Met-triggered signaling pathways that regulate hepatocyte survival during embryogenesis. Here, we show that PI3K acts via mTOR (Frap1) to regulate p53 activity both in vitro and in vivo. mTOR inhibits p53 by promoting the translation of Mdm2, a negative regulator of p53. We also demonstrate that the PI3K effector Akt is required for Met-triggered Mdm2 upregulation, in addition to being necessary for the nuclear translocation of Mdm2. Inhibition of either mTOR or Mdm2 is sufficient to block cell survival induced by Hgf-Met in vitro. Moreover, in vivo inhibition of mTOR downregulates Mdm2 protein levels and induces p53-dependent apoptosis. Our studies identify a novel mechanism for Met-triggered cell survival during embryogenesis, involving translational regulation of Mdm2 by mTOR. Moreover, they reinforce mTOR as a potential drug target in cancer.
Moumen
Anice
A
Developmental Biology Institute of Marseille-Luminy (IBDML CNRS-INSERM-Université de la Méditerrannée, Campus de Luminy-Case 907, 13288 Marseille Cedex 09, France.
Patané
Salvatore
S
Porras
Almudena
A
Dono
Rosanna
R
Maina
Flavio
F
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D011494:Protein Kinases / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D011494:Protein Kinases; C546843:mTOR protein, mouse; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases