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EMBO J. 2017 Aug 1;36(15):2280-2295. doi: 10.15252/embj.201695553. Epub 2017 Jun 12.

p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling.

Author information

1
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
2
Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot, Israel.
3
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel valery.krizhanovsky@weizmann.ac.il.

Abstract

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)-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.

KEYWORDS:

JNK ; DNA damage response; apoptosis; cellular senescence; p21(CDKN1A)

PMID:
28607003
PMCID:
PMC5538795
DOI:
10.15252/embj.201695553
[Indexed for MEDLINE]
Free PMC Article

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