Abstract
Solar ultraviolet (UV) A radiation is a well known trigger of signaling responses in human skin fibroblasts. One important consequence of this stress response is the increased expression of matrix metalloproteinase-1 (MMP-1), which causes extracellular protein degradation and thereby contributes to photoaging of human skin. In the present study we identify the proteasome as an integral part of the UVA-induced, intracellular signaling cascade in human dermal fibroblasts. UVA-induced singlet oxygen formation was accompanied by protein oxidation, the cross-linking of oxidized proteins, and an inhibition of the proteasomal system. This proteasomal inhibition subsequently led to an accumulation of c-Jun and phosphorylated c-Jun and activation of activator protein-1, i.e. transcription factors known to control MMP-1 expression. Increased transcription factor activation was also observed if the proteasome was inhibited by cross-linked proteins or lactacystin, indicating a general mechanism. Most importantly, inhibition of the proteasome was of functional relevance for UVA-induced MMP-1 expression, because overexpression of the proteasome or the protein repair enzyme methionine sulfoxide reductase prevented the UVA-induced induction of MMP-1. These studies show that an environmentally relevant stimulus can trigger a signaling pathway, which links intracellular and extracellular protein degradation. They also identify the proteasome as an integral part of the UVA stress response.
Highlights
Umwelt (German Federal Ministry for the Environment, Nature Conservation, and Nuclear Safety), and by European Cooperation in Science and Technology B35
In the present study we show that ultraviolet A (UVA) radiation, through a singlet oxygen-mediated mechanism, causes protein oxidation and attenuation of proteasome activity in human skin fibroblasts
In this study we have found that UVA irradiation causes a loss in proteasome activity by way of protein oxidation followed by aggregate formation
Summary
In the present study we show that UVA radiation, through a singlet oxygen-mediated mechanism, causes protein oxidation and attenuation of proteasome activity in human skin fibroblasts. This leads to the decreased degradation of intracellular proteins including constituents of the transcription factor complex AP-1 and to increased MMP-1 transcription. Our studies identify the proteasome as an integral part of the UVA stress response and link intracellular and extracellular protein degradation
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