Activation of c-Jun N-terminal kinase 1 by UV irradiation is inhibited by wortmannin without affecting c-jun expression

Activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kina ses is an early response of cells upon exposure to DNA-damaging agents. JNK -mediated phosphorylation of c-Jun is currently understood to stimulate the transactivating potency of AP-1 (e.g., c-Jun/c-Fos; c-Jun/ATF-2), thereby increasing the expression of AP-1 target genes. Here we show that stimulati on of JNK1 activity is not a general early response of cells exposed to gen otoxic agents. Treatment of NIH 3T3 cells with UV light (UV-C) as well as w ith methyl methanesulfonate (MMS) caused activation of JNK1 and an increase in c-Jun protein and AP-1 binding activity, whereas antineoplastic drugs s uch as mafosfamide, mitomycin C, N-hydroxyethyl-N-chloroethylnitrosourea, a nd treosulfan did not elicit this response. The phosphatidylinositol 3-kina se inhibitor wortmannin specifically blocked the UV-stimulated activation o f JNK1 but did not affect UV-driven activation of extracellular regulated k inase 2 (ERK2). To investigate the significance of JNK1 for transactivation of c-jun, we analyzed the effect of UV irradiation on c-jun expression und er conditions of wortmannin-mediated inhibition of W-induced stimulation of JNK1. Neither the UV-induced increase in c-jun mRNA, c-Jun protein, and AP -1 binding nor the activation of the collagenase and c-jun promoters was af fected by wortmannin. In contrast, the mitogen-activated protein kinase/ERK kinase inhibitor PD98056, which blocked ERK2 but not JNK1 activation by UV irradiation, impaired UV-driven c-Jun protein induction and AP-1 binding. Based on the data, we suggest that JNK1 stimulation is not essential for tr ansactivation of c-jun after UV exposure, whereas activation of ERK2 is req uired for UV-induced signaling leading to elevated c-jun expression.