S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response.
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 p38alpha 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.
Lai
Keng Po
KP
Division of Cancer and Developmental Biology, Institute of Molecular and Cell Biology, Singapore.
Leong
Wai Fook
WF
Chau
Jenny Fung Ling
JF
Jia
Deyong
D
Zeng
Li
L
Liu
Huijuan
H
He
Lin
L
Hao
Aijun
A
Zhang
Hongbing
H
Meek
David
D
Velagapudi
Chakradhar
C
Habib
Samy L
SL
Li
Baojie
B
D002453:Cell Cycle; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1