最先端研究セミナー

講演者：　 田畑　祥（国立がん研究センター・鶴岡連携研究拠点 がんメタボロミクス研究室 外来研究員）

演題：　NFκB nuclear dynamics orchestrate inflammatory aging

日時： 2023年10月18日（水）12:00- 13:00

Abstract:

Inflammatory aging, the chronic inflammation associated with aging, is a critical factor in the induction of a wide range of human age-related diseases and its regulation is becoming increasingly important in aging societies. Elderly individuals exhibit low-grade and persistent chronic inflammation in their tissues along with elevated levels of circulating inflammatory factors that activate nuclear factor κB (NFκB) signaling, such as interleukin-6 and tumor necrosis factor α (TNFα). NFκB is an important transcription factor that has been implicated in various biological phenomena such as cancer, inflammation, aging, and immune response. Excessive NFκB activity induces pathological inflammation and contributes to the progression of several human diseases. The canonical signaling pathway of NFκB has multiple feedbacks, and activation of NFκB is known to exhibit oscillatory behavior. NFκB inhibitor α (IκBα) is one of the target genes of NFκB, but also mediates a strong negative feedback loop that can remove NFκB from DNA and lead to oscillatory NFκB activity. Downregulation of the IκBα expression induces sustained NFκB activation in cells stimulated with TNFα, resulting in gene expression distinct from oscillatory NFκB activation (1). However, whether and how this change in the dynamics of NFκB activity is related to cell properties or fate has not been fully addressed.

In this study, we show through mathematical modeling and experiments that dysfunction of the negative feedback regulators of NFκB, IκBα and A20, alters NFκB nuclear dynamics from oscillatory to sustained, promoting cellular senescence by remodeling the epigenetic regulatory and metabolic landscape (2). In this talk, we would like to discuss the molecular mechanisms of cellular senescence caused by the altered dynamics of NFκB activity due to IκBα knockdown.