Sustained activation of NF-κB through constitutively active IKKβ leads to senescence bypass in murine dermal fibroblasts.

IF 3.4 3区 生物学 Q3 CELL BIOLOGY
Cell Cycle Pub Date : 2024-02-01 Epub Date: 2024-03-10 DOI:10.1080/15384101.2024.2325802
Masayuki Harada, Kanae Su-Harada, Takeshi Kimura, Koh Ono, Noboru Ashida
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引用次数: 0

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.

通过组成型活性 IKKβ持续激活 NF-κB,导致小鼠真皮成纤维细胞衰老旁路。
尽管转录因子核因子κB(NF-κB)在衰老相关分泌表型(SASP)获得的调控中起着核心作用,但我们对 NF-κB 参与诱导细胞衰老的了解却很有限。在这里,我们发现激活典型的 NF-κB 通路能抑制小鼠真皮成纤维细胞的衰老。衰老相关的β-半乳糖苷酶(SA-β-gal)染色和p16INK4a mRNA水平表明,缺失IκB激酶β(IKKβ)的真皮成纤维细胞的NF-κB激活无效,在20%氧条件下培养时比对照细胞衰老更快。相反,组成型活性 IKKβ(IKKβ-CA)的表达足以驱动衰老旁路。值得注意的是,抑制 NF-κB 核转位的κB 抑制剂(IκB)的抗降解形式的表达取消了衰老旁路,这表明 IKKβ-CA 对衰老的抑制作用主要是由 NF-κB 介导的。我们还发现,IKKβ-CA的表达抑制了INK4/Arf基因的去抑制作用,并抵消了与衰老相关的多聚核抑制复合体2(PRC2)催化亚基Ezh2的损失。此外,药理抑制 Ezh2 可消除 IKKβ-CA 诱导的衰老旁路。我们认为,NF-κB通过维持Ezh2的表达,在应激诱导的衰老诱导过程中发挥了抑制作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Cycle
Cell Cycle 生物-细胞生物学
CiteScore
7.70
自引率
2.30%
发文量
281
审稿时长
1 months
期刊介绍: Cell Cycle is a bi-weekly peer-reviewed journal of high priority research from all areas of cell biology. Cell Cycle covers all topics from yeast to man, from DNA to function, from development to aging, from stem cells to cell senescence, from metabolism to cell death, from cancer to neurobiology, from molecular biology to therapeutics. Our goal is fast publication of outstanding research.
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