Sequential DNA damage-independent and -dependent activation of NF-kappa B by UV

Abstract

NF‐κB activation in response to UV irradiation of HeLa cells or of primary human skin fibroblasts occurs with two overlapping kinetics but totally different mechanisms. Although both mechanisms involve induced dissociation of NF‐κB from IκBα and degradation of IκBα, targeting for degradation and signaling are different. Early IκBα degradation at 30 min to ∼6 h is not initiated by UV‐induced DNA damage. It does not require IκB kinase (IKK), as shown by introduction of a dominant‐negative kinase subunit, and does not depend on the presence of the phosphorylatable substrate, IκBα, carrying serines at positions 32 and 36. Induced IκBα degradation requires, however, intact N‐ (positions 1–36) and C‐terminal (positions 277–287) sequences. IκB degradation and NF‐κB activation at late time points, 15–20 h after UV irradiation, is mediated through DNA damage‐induced cleavage of IL‐1α precursor, release of IL‐1α and autocrine/paracrine action of IL‐1α. Late‐induced IκBα requires the presence of Ser32 and Ser36. The late mechanism indicates the existence of signal transfer from photoproducts in the nucleus to the cytoplasm. The release of the ‘alarmone’ IL‐1α may account for some of the systemic effects of sunlight exposure.