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S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response

Keng Po Lai1, Wai Fook Leong, Jenny Fung Ling Chau

  • 1Division of Cancer and Developmental Biology, Institute of Molecular and Cell Biology, Singapore.

The EMBO Journal
|July 27, 2010
PubMed

Insights

The mTOR-S6K1 pathway regulates the tumor suppressor p53 during DNA damage. Activated S6K1 inhibits Mdm2, preventing p53 degradation and promoting cell cycle arrest, impacting cancer and aging.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • p53 is a crucial tumor suppressor that controls cell-cycle arrest, apoptosis, and senescence in response to DNA damage.
  • Mdm2 negatively regulates p53 by promoting its ubiquitination, nuclear export, and degradation.
  • The precise mechanisms controlling Mdm2 activity under genotoxic stress are not fully understood.

Purpose of the Study:

  • To identify kinases phosphorylating Mdm2 on S163 under genotoxic stress.
  • To elucidate the role of the identified kinase in regulating p53 stability and DNA damage response.
  • To establish the connection between metabolic signaling and p53 regulation.

Main Methods:

  • Investigated kinases responsible for Mdm2 S163 phosphorylation during genotoxic stress.
  • Utilized molecular biology techniques to study the mTOR-S6K1 pathway activation by p38alpha MAPK.
  • Analyzed the interaction between S6K1 and Mdm2, and their effects on p53 ubiquitination and induction.

Main Results:

  • Identified S6K1 as a key kinase phosphorylating Mdm2 on S163.
  • DNA damage activates mTOR-S6K1 signaling, which enhances the S6K1-Mdm2 complex formation.
  • Activated S6K1 inhibits Mdm2-mediated p53 ubiquitination, leading to increased p53 levels and induction.

Conclusions:

  • mTOR-S6K1 is a novel regulator of p53 in the DNA damage response, influencing cell death.
  • The S6K1-Mdm2 interaction integrates metabolic cues into the DNA damage response pathway.
  • This pathway links the Mdm2-p53 axis, involved in aging, with the mTOR-S6K pathway, suggesting implications in tumorigenesis.

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