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 phenotype of tumor cells by facilitating extracellular matrix hydrolysis. However, the molecular mechanism(s) responsible for urokinase overexpression remains unclear. The current study was undertaken to determine the role of the p53 tumor suppressor gene in the regulation of urokinase expression. Transient cob transfection of a urokinase-producing cell line with a wildtype p53 expression vector and a CAT reporter driven by the urokinase promoter led to a dramatic reduction in CAT activity. Conversely, urokinase promoter activity was increased in cells transiently transfected with a p53 expression vector mutated at codon 175. To determine if the endogenous urokinase gene was modulated by p53, cells were stably transfected with a mutated p53-bearing expression vector. An increased level of urokinase mRNA was apparent in pooled mutant p53-overexpressing clones. These studies argue for a role of the p53 tumor suppressor gene in the regulation of urokinase expression.