| First Author | Harada M | Year | 2024 |
| Journal | Cell Cycle | Volume | 23 |
| Issue | 3 | Pages | 308-327 |
| PubMed ID | 38461418 | Mgi Jnum | J:353685 |
| Mgi Id | MGI:7705620 | Doi | 10.1080/15384101.2024.2325802 |
| Citation | Harada M, et al. (2024) Sustained activation of NF-kappaB through constitutively active IKKbeta leads to senescence bypass in murine dermal fibroblasts. Cell Cycle 23(3):308-327 |
| abstractText | Although the transcription factor nuclear factor kappaB (NF-kappaB) plays a central role in the regulation of senescence-associated secretory phenotype (SASP) acquisition, our understanding of the involvement of NF-kappaB in the induction of cellular senescence is limited. Here, we show that activation of the canonical NF-kappaB pathway suppresses senescence in murine dermal fibroblasts. IkappaB kinase beta (IKKbeta)-depleted dermal fibroblasts showed ineffective NF-kappaB activation and underwent senescence more rapidly than control cells when cultured under 20% oxygen conditions, as indicated by senescence-associated beta-galactosidase (SA-beta-gal) staining and p16(INK4a) mRNA levels. Conversely, the expression of constitutively active IKKbeta (IKKbeta-CA) was sufficient to drive senescence bypass. Notably, the expression of a degradation-resistant form of inhibitor of kappaB (IkappaB), which inhibits NF-kappaB nuclear translocation, abolished senescence bypass, suggesting that the inhibitory effect of IKKbeta-CA on senescence is largely mediated by NF-kappaB. We also found that IKKbeta-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 IKKbeta-CA-induced senescence bypass. We propose that NF-kappaB plays a suppressive role in the induction of stress-induced senescence through sustaining Ezh2 expression. |
