Journal
EMBO JOURNAL
Volume 36, Issue 15, Pages 2280-2295Publisher
WILEY
DOI: 10.15252/embj.201695553
Keywords
apoptosis; cellular senescence; DNA damage response; JNK; p21 (CDKN1A)
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Funding
- European Research Council under European Union
- Israel Science Foundation
- Bruce Kanter Fund
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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 (CDKN1A) 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)-kappa B kinase, leading to decreased cell survival. NF-kappa B activation induced TNF-alpha 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.
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