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ZRF 1 is a novel S6 kinase substrate that drives the senescence programme
Author(s) -
Barilari Manuela,
Bonfils Gregory,
Treins Caroline,
Koka Vonda,
De Villeneuve Delphine,
Fabrega Sylvie,
Pende Mario
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201694966
Subject(s) - art , humanities
The inactivation of S6 kinases mimics several aspects of caloric restriction, including small body size, increased insulin sensitivity and longevity. However, the impact of S6 kinase activity on cellular senescence remains to be established. Here, we show that the constitutive activation of mammalian target of rapamycin complex 1 ( mTORC 1) by tuberous sclerosis complex ( TSC ) mutations induces a premature senescence programme in fibroblasts that relies on S6 kinases. To determine novel molecular targets linking S6 kinase activation to the control of senescence, we set up a chemical genetic screen, leading to the identification of the nuclear epigenetic factor ZRF 1 (also known as DNAJC 2, MIDA 1, Mpp11). S6 kinases phosphorylate ZRF 1 on Ser47 in cultured cells and in mammalian tissues in vivo . Knock‐down of ZRF 1 or expression of a phosphorylation mutant is sufficient to blunt the S6 kinase‐dependent senescence programme. This is traced by a sharp alteration in p16 levels, the cell cycle inhibitor and a master regulator of senescence. Our findings reveal a mechanism by which nutrient sensing pathways impact on cell senescence through the activation of mTORC 1‐S6 kinases and the phosphorylation of ZRF 1.