UV IRRADIATION INDUCES THE MURINE UROKINASE-TYPE PLASMINOGEN-ACTIVATOR GENE VIA THE C-JUN N-TERMINAL KINASE SIGNALING PATHWAY - REQUIREMENTOF AN AP1 ENHANCER ELEMENT

UV irradiation leads to severe damage, such as cutaneous inflammation, immunosuppression, and cancer, but it also results in a gene inductio n protective response termed the UV response. The signal triggering th e UV response was thought to originate from DNA damage; recent finding s, however, have shown that it is initiated at or near the cell membra ne and transmitted via cytoplasmic kinase cascades to induce gene tran scription. Urokinase-type plasminogen activator (uPA) was the first pr otein shown to be UV inducible in xeroderma pigmentosum DNA repair-def icient human cells. However, the underlying molecular mechanisms respo nsible for the induction were not elucidated. We have found that the e ndogenous murine uPA gene product is transcriptionally upregulated by UV in NIH 3T3 fibroblast and F9 teratocarcinoma cells. This induction required an activator protein 1 (AP1) enhancer element located at -2.4 kb, since deletion of this site abrogated the induction. We analyzed the contribution of the three different types of UV-inducible mitogen- activated protein (MAP) kinases (ERK, JNK/SAPK, and p38) to the activa tion of the murine uPA promoter by UV, MEKK1, a specific JNK activator , induced transcription from the uPA promoter in the absence of UV tre atment, whereas coexpression of catalytically inactive MEKK1(K432M) an d of cytoplasmic JNK inhibitor JIP-1 inhibited W-induced uPA transcrip tional activity. In contrast, neither dominant negative MKK6 (or SB203 580) nor PD98059, which specifically inhibit p38 and ERK MAP kinase pa thways, respectively, could abrogate the UV-induced effect. Moreover, our results indicated that wild-type N-terminal c-Jun, but not mutated c-Jun (Ala-63/73), was able to mediate UV-induced uPA transcriptional activity. Taken together, we show for the first time that kinases of the JNK family can activate the uPA promoter. This activation links ex ternal UV stimulation and AP1-dependent uPA transcription, providing a transcription-coupled signal transduction pathway for the induction o f the murine uPA gene by UV.