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p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling
Author(s) -
Yosef Reut,
Pilpel Noam,
Papismadov Nurit,
Gal Hilah,
Ovadya Yossi,
Vadai Ezra,
Miller Stav,
Porat Ziv,
BenDor Shifra,
Krizhanovsky Valery
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.201695553
Subject(s) - biology , microbiology and biotechnology , dna damage , viability assay , programmed cell death , kinase , senescence , carcinogenesis , cell cycle , checkpoint kinase 2 , cell , cancer research , apoptosis , protein kinase a , dna , cancer , biochemistry , genetics , protein serine threonine kinases
Cellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. However, accumulation of senescent cells in tissues during aging contributes to age‐related pathologies. A deeper understanding of the mechanisms regulating the viability of senescent cells is therefore required. Here, we show that the CDK inhibitor p21 ( CDKN 1A) maintains the viability of DNA damage‐induced senescent cells. Upon p21 knockdown, senescent cells acquired multiple DNA lesions that activated ataxia telangiectasia mutated ( ATM ) and nuclear factor ( NF )‐κB kinase, leading to decreased cell survival. NF ‐κB activation induced TNF ‐α secretion and JNK activation to mediate death of senescent cells in a caspase‐ and JNK ‐dependent manner. Notably, p21 knockout in mice eliminated liver senescent stellate cells and alleviated liver fibrosis and collagen production. These findings define a novel pathway that regulates senescent cell viability and fibrosis.