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

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
ACS Applied Electronic Materials 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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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
CiteScore
7.20
自引率
4.30%
发文量
567
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