Impairment of the EGF signaling pathway by the oxidative stress generated with UVA.

Abstract

Ultraviolet A (UVA) is a component of sunlight reaching the surface of the earth and involved in photodegenerescence and photocarcinogenesis. The effect of UVA was investigated on the EGF-induced activation of the signaling kinase ERK and the transcription factors AP1, NFkappaB, and STAT1. UVA prevented the Epidermal Growth Factor (EGF)-induced stimulation of ERK in a dose-dependent manner within the range of 1.5-9 J/cm(2). Concomitantly, the DNA binding activity of AP1, NFkappaB, and STAT1 under EGF were markedly inhibited by UVA within the same dose range. UVA by itself induced an activation of ERK activity, and a stimulation of AP1, NFkappaB, and STAT1 binding activity. UVA decreased EGF binding in a dose-dependent manner. Furthermore, the highest dose of UVA (9 J/cm(2)) prevented the EGF-induced Tyr-phosphorylation of the EGF-receptor (EGF-R). The generation of reactive oxygen species (ROS), as assessed by the fluorescent probe dichloro-fluorescein, showed an additive effect of EGF and UVA, within the studied range of UVA doses. Finally, the antioxidant Vitamin E prevented the inhibitory effect of UVA on ERK, AP1, NFkappaB, and STAT1. These results demonstrate that an overproduction of ROS, initiated by two different and successive triggering agents such as UVA and EGF, leads to inactivation of the EGF signaling pathway. This inhibition of gene expression control by EGF might play a role in the photodegenerative processes observed after exposition of skin cells to solar radiation.