Abstract
Although the transcription factor nuclear factor κB (NF-κB) plays a central role in the regulation of senescence-associated secretory phenotype (SASP) acquisition, our understanding of the involvement of NF-κB in the induction of cellular senescence is limited. Here, we show that activation of the canonical NF-κB pathway suppresses senescence in murine dermal fibroblasts. IκB kinase β (IKKβ)-depleted dermal fibroblasts showed ineffective NF-κB activation and underwent senescence more rapidly than control cells when cultured under 20% oxygen conditions, as indicated by senescence-associated β-galactosidase (SA-β-gal) staining and p16INK4a mRNA levels. Conversely, the expression of constitutively active IKKβ (IKKβ-CA) was sufficient to drive senescence bypass. Notably, the expression of a degradation-resistant form of inhibitor of κB (IκB), which inhibits NF-κB nuclear translocation, abolished senescence bypass, suggesting that the inhibitory effect of IKKβ-CA on senescence is largely mediated by NF-κB. We also found that IKKβ-CA expression suppressed the derepression of INK4/Arf genes and counteracted the senescence-associated loss of Ezh2, a catalytic subunit of the Polycomb repressive complex 2 (PRC2). Moreover, pharmacological inhibition of Ezh2 abolished IKKβ-CA-induced senescence bypass. We propose that NF-κB plays a suppressive role in the induction of stress-induced senescence through sustaining Ezh2 expression.
Keywords:
IκB kinase β; Senescence bypass; nuclear factor κb.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Cellular Senescence* / drug effects
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Cyclin-Dependent Kinase Inhibitor p16* / genetics
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Cyclin-Dependent Kinase Inhibitor p16* / metabolism
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Enhancer of Zeste Homolog 2 Protein / genetics
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Enhancer of Zeste Homolog 2 Protein / metabolism
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Fibroblasts* / metabolism
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I-kappa B Kinase* / genetics
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I-kappa B Kinase* / metabolism
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Mice
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NF-kappa B* / metabolism
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Polycomb Repressive Complex 2 / genetics
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Polycomb Repressive Complex 2 / metabolism
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Signal Transduction
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse
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I-kappa B Kinase
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NF-kappa B
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Polycomb Repressive Complex 2
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Nfkb1 protein, mouse
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Ikbkb protein, mouse
Grants and funding
This research was supported by AMED under Grant Number DNW-19009 and DNW-20021.