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

Masayuki Harada1, Kanae Su-Harada1, Takeshi Kimura1

  • 1Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Cell Cycle (Georgetown, Tex.)
|March 10, 2024
PubMed

Insights

Nuclear factor κB (NF-κB) activation suppresses cellular senescence by maintaining Ezh2 expression. Inhibiting IκB kinase β (IKKβ) accelerates senescence, while activating IKKβ bypasses it, highlighting NF-κB

Area of Science:

  • Cellular senescence and aging research
  • Molecular biology and epigenetics
  • NF-κB signaling pathway

Background:

  • Nuclear factor κB (NF-κB) is crucial for senescence-associated secretory phenotype (SASP) but its role in senescence induction is unclear.
  • Cellular senescence is a complex process with implications for aging and cancer.
  • The canonical NF-κB pathway involves IκB kinase β (IKKβ) and inhibitor of κB (IκB).

Purpose of the Study:

  • To investigate the role of the canonical NF-κB pathway in the induction of cellular senescence.
  • To determine how IKKβ and NF-κB signaling influence senescence in fibroblasts.
  • To elucidate the molecular mechanisms by which NF-κB affects senescence, including its interaction with Ezh2 and INK4/Arf genes.

Main Methods:

  • Depletion of IKKβ in murine dermal fibroblasts to assess senescence induction under 20% oxygen.
  • Expression of constitutively active IKKβ (IKKβ-CA) to evaluate senescence bypass.
  • Inhibition of NF-κB nuclear translocation using a degradation-resistant IκB.
  • Analysis of senescence markers (SA-β-gal, p16 mRNA) and gene expression (INK4/Arf, Ezh2).
  • Pharmacological inhibition of Ezh2 to confirm its role in IKKβ-mediated senescence bypass.

Main Results:

  • IKKβ-depleted fibroblasts exhibited accelerated senescence, indicating impaired NF-κB activation.
  • Constitutively active IKKβ (IKKβ-CA) expression led to senescence bypass.
  • NF-κB activation was essential for IKKβ-CA-induced senescence bypass.
  • IKKβ-CA suppressed INK4/Arf gene derepression and maintained Ezh2 expression.
  • Ezh2 inhibition abolished IKKβ-CA-induced senescence bypass.

Conclusions:

  • The canonical NF-κB pathway, activated by IKKβ, plays a suppressive role in stress-induced cellular senescence.
  • NF-κB signaling inhibits senescence, at least partly, by sustaining Ezh2 expression.
  • These findings reveal a novel mechanism linking NF-κB, Ezh2, and senescence regulation.
Keywords:
IκB kinase βSenescence bypassnuclear factor κb

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