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.
Highlights
Cellular senescence, a permanent form of cell cycle arrest, halts cell proliferation in response to various stressors, including telomere shortening, oncogene activation, and DNA damage (Kuilman et al, 2010; Campisi, 2013; Munoz-Espin & Serrano, 2014; Salama et al, 2014)
We found that following p21 knockdown, senescent cells sustain multiple DNA lesions, leading to further activation of DNA damage response and nuclear factor (NF)-jB pathways
In view of the extensive DNA damage response (DDR) that we observed after p21 knockdown in damage-induced senescence (DIS) cells, we evaluated activation of the above tumor necrosis factor (TNF)-a-driven pathway in these cells
Summary
A permanent form of cell cycle arrest, halts cell proliferation in response to various stressors, including telomere shortening, oncogene activation, and DNA damage (Kuilman et al, 2010; Campisi, 2013; Munoz-Espin & Serrano, 2014; Salama et al, 2014). Accumulation of ECM leads to fibrosis, which aims to maintain tissue integrity while the healing process is taking place These activated HSCs subsequently undergo senescence, accompanied by a decline in ECM production and an increase in SASP factors that facilitate elimination of these cells by natural killer (NK) cells (Krizhanovsky et al, 2008). The p53 target p21, via its ability to promote cell cycle inhibition, can protect some cells from apoptosis (Abbas & Dutta, 2009) This effect might be governed by both p53-dependent and -independent upregulation of the pro-apoptotic protein BAX, or by activation of members of the tumor necrosis factor (TNF)-a family of death receptors, or by effects on DNA repair (Abbas & Dutta, 2009). These results uncovered new mechanisms that control the fate of senescent cells
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