Disruption of cytoskeletal structures results in the induction of the urokinase-type plasminogen activator gene expression.

Urokinase-type plasminogen activator (uPA) is expressed at higher levels in many transformed cells as compared with their non-transformed counterparts. The transformed phenotype is associated with changes in the cytoskeleton. Therefore, we have investigated whether alterations in the cytoskeleton can trigger changes in the expression of the uPA gene. To this end we analyzed the expression of the uPA gene following exposure of porcine kidney cells, LLC-PK1, to agents that modify the organization of specific components of the cytoskeleton. These cells exhibited increased uPA mRNA and protein after disruption of microtubules by colchicine or nocodazole treatment or after disruption of microfilaments by cytochalasin B treatment. Colchicine, nocodazole, and cytochalasin B did not cause alterations in the level of cAMP-dependent protein kinase in LLC-PK1 cells. In contrast, down-regulation of protein kinase C by phorbol myristate acetate, reduced, but did not fully prevent the induction of uPA mRNA when LLC-PK1 cells were subsequently exposed to colchicine, nocodazole, or cytochalasin B. Apparently, a signal transduction pathway in part involving protein kinase C but not cAMP-protein kinase mediates the regulatory changes at the transcriptional level of the uPA gene. Inhibition of protein synthesis by cycloheximide prior to the exposure of LLC-PK1 cells to colchicine, nocodazole, or cytochalasin B, largely prevented the induction of uPA mRNA.