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

Keng Po Lai, Wai Fook Leong, Jenny Fung Ling Chau, Deyong Jia, Li Zeng, Huijuan Liu, Lin He, Aijun Hao, Hongbing Zhang, David Meek, Chakradhar Velagapudi, Samy L. Habib, Baojie Li

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    73 Citations (Scopus)

    Abstract

    p53 mediates DNA damage-induced cell-cycle arrest, apoptosis, or senescence, and it is controlled by Mdm2, which mainly ubiquitinates p53 in the nucleus and promotes p53 nuclear export and degradation. By searching for the kinases responsible for Mdm2 S163 phosphorylation under genotoxic stress, we identified S6K1 as a multifaceted regulator of Mdm2. DNA damage activates mTOR-S6K1 through p38 alpha MAPK. The activated S6K1 forms a tighter complex with Mdm2, inhibits Mdm2-mediated p53 ubiquitination, and promotes p53 induction, in addition to phosphorylating Mdm2 on S163. Deactivation of mTOR-S6K1 signalling leads to Mdm2 nuclear translocation, which is facilitated by S163 phosphorylation, a reduction in p53 induction, and an alteration in p53-dependent cell death. These findings thus establish mTOR-S6K1 as a novel regulator of p53 in DNA damage response and likely in tumorigenesis. S6K1-Mdm2 interaction presents a route for cells to incorporate the metabolic/energy cues into DNA damage response and links the aging-controlling Mdm2-p53 and mTOR-S6K pathways. The EMBO Journal (2010) 29, 2994-3006. doi: 10.1038/emboj.2010.166; Published online 23 July 2010

    Original languageEnglish
    Pages (from-to)2994-3006
    Number of pages13
    JournalEMBO Journal
    Volume29
    Issue number17
    DOIs
    Publication statusPublished - 1 Sep 2010

    Keywords

    • Mdm2
    • nuclearcytoplasmic shuttling
    • p53
    • S6K1
    • INSULIN-RESISTANCE
    • GENE-PRODUCTS
    • LIFE-SPAN
    • P53
    • MTOR
    • KINASE
    • PHOSPHORYLATION
    • CANCER
    • CELL
    • ACTIVATION

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