MODULATION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR EXPRESSION BY THE WILD-TYPE AND MUTATED P53 TUMOR-SUPPRESSOR GENE

The urokinase-type plasminogen activator contributes to the invasive p henotype of tumor cells by facilitating extracellular matrix hydrolysi s. However, the molecular mechanism(s) responsible for urokinase overe xpression remains unclear. The current study was undertaken to determi ne the role of the p53 tumor suppressor gene in the regulation of urok inase expression. Transient cob transfection of a urokinase-producing cell line with a wildtype p53 expression vector and a CAT reporter dri ven by the urokinase promoter led to a dramatic reduction in CAT activ ity. Conversely, urokinase promoter activity was increased in cells tr ansiently transfected with a p53 expression vector mutated at codon 17 5. To determine if the endogenous urokinase gene was modulated by p53, cells were stably transfected with a mutated p53-bearing expression v ector. An increased level of urokinase mRNA was apparent in pooled mut ant p53-overexpressing clones. These studies argue for a role of the p 53 tumor suppressor gene in the regulation of urokinase expression.