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Met acts on Mdm2 via mTOR to signal cell survival during development

Anice Moumen¹, Salvatore Patané, Almudena Porras

¹Developmental Biology Institute of Marseille-Luminy (IBDML CNRS-INSERM-Université de la Méditerrannée, Campus de Luminy-Case 907, 13288 Marseille Cedex 09, France.

Development (Cambridge, England)

|March 3, 2007

Abstract:

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.

Insights

The Met receptor pathway regulates cell survival during embryonic development by controlling the translation of Mdm2, a p53 regulator, via mTOR signaling. This pathway

Area of Science:

Cell Biology
Developmental Biology
Molecular Biology

Background:

Cell death and survival balance is critical for development and health, with dysregulation linked to cancer.
Growth factor receptors like Met activate phosphatidyl-inositol-3' kinase (PI3K), a key mediator of cell growth and survival.
PI3K can counteract p53-induced cell death, but the precise mechanisms remain unclear.

Purpose of the Study:

To investigate the Met-triggered signaling pathways governing hepatocyte survival during embryogenesis.
To elucidate the molecular mechanisms by which PI3K signaling influences p53 activity and cell fate.

Main Methods:

Utilized genetic and pharmacological approaches for in vitro and in vivo studies.
Investigated the roles of PI3K, mTOR (Frap1), Akt, and Mdm2 in Met signaling.
Assessed p53 activity, Mdm2 translation, and apoptosis induction.

Main Results:

PI3K signaling regulates p53 activity through mTOR (Frap1).
mTOR promotes Mdm2 translation, a negative regulator of p53.
Akt is essential for Met-induced Mdm2 upregulation and nuclear translocation.
Inhibition of mTOR or Mdm2 blocks Met-driven cell survival; in vivo mTOR inhibition induces apoptosis.

Conclusions:

Identified a novel mechanism of Met-triggered cell survival during embryogenesis involving mTOR-mediated translational control of Mdm2.
Reinforced mTOR as a potential therapeutic target for cancer treatment.

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