REGULATION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR EXPRESSION BY THE V-MOS ONCOGENE

We undertook a study to determine if the serine-threonine kinase-encod ing v-mos oncogene regulated the expression of the urokinase-type plas minogen activator. An expression vector encoding v-mos, but not a kina se-inactive mutant, stimulated urokinase promoter activity in CAT assa ys employing a squamous cell carcinoma cell line, The induction of uro kinase promoter activity by v-mos was mediated, in part, via an increa sed AP-1 activity since (a) mutation of 2 AP-1 binding sites (at -1967 and -1885), or the co-expression of a transactivation domain-lacking c-jun mutant reduced the induction of the urokinase promoter by v-mos and (b) expression of v-mos increased the activity of a CAT reporter d riven by three AP-1 tandem repeats, The stimulation of the urokinase p romoter by v-mos was partially countered by co-expression of an ERK1/E RK2-inactivating phosphatase. Western blotting and zymographic analysi s indicated that v-mos-transformed NM3T3 cells (MSV NIH-3T3) secreted more urokinase compared with NIH3T3 cells and this was associated with a higher level of activated ERK1 and ERK2, Expression of a catalytica lly-inactive MAPKK mutant reduced the activity of a urokinase promoter -driven CAT reporter in the MSV NIH-3T3 cells, In conclusion, the data herein indicate that urokinase expression is regulated by v-mos throu gh a MAPKK-dependent signaling pathway.