Development 2007,
PMID: 17329361
Moumen, Anice; Patané, Salvatore; Porras, Almudena; Dono, Rosanna; Maina, Flavio
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.
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Text Mining Data
Dashed line = No text mining data
Manually curated Databases
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OpenBEL Selventa BEL large corpus:
TP53
(decreases, Activity, TP53 Activity)
Evidence: PI3K can then antagonize p53-triggered cell death, but the underlying mechanisms are not fully understood.
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OpenBEL Selventa BEL large corpus:
MDM2
→
MET
(increases)
Evidence: 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.
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NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
mTORC1 complex (MTOR-MLST8-RPTOR)
→
4E-BP1/eIF4E complex (EIF4EBP1-EIF4E)
(modification, activates)
Evidence: mutant phenotype, assay
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NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
mTORC1 complex (MTOR-MLST8-RPTOR)
→
DEPTOR (DEPTOR)
(modification, collaborate)
Evidence: mutant phenotype
-
NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
mTORC1 complex (MTOR-MLST8-RPTOR)
→
PRAS40 (AKT1S1)
(modification, collaborate)
Evidence: mutant phenotype
-
NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
mTORC1 complex (MTOR-MLST8-RPTOR)
→
mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR)
(modification, collaborate)
Evidence: mutant phenotype
-
NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
DEPTOR (DEPTOR)
→
PRAS40 (AKT1S1)
(modification, collaborate)
Evidence: mutant phenotype
-
NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
DEPTOR (DEPTOR)
→
mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR)
(modification, collaborate)
Evidence: mutant phenotype
-
NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
PRAS40 (AKT1S1)
→
mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR)
(modification, collaborate)
Evidence: mutant phenotype
-
NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met):
mTORC1/PRAS40/DEPTOR complex (MTOR-MLST8-AKT1S1-DEPTOR-RPTOR)
→
AKT1-2-active (AKT1/AKT2)
(modification, collaborate)
Evidence: mutant phenotype
In total, 32 gene pairs are associated to this article in curated databases