Phorbol Ester Stimulated Cathepsin I Expression

Abstrad Cathepsin I (dsl) is a lysosomal cysteine proteinase, the synthesis and secretion of which is induced by transformation, growth fadors, and tumor promoters. We studied the effed and the mechanism of adion of phorbol ester (TPA) on the expression of ctsl mRNA in U937 histiocytic leukemia cells. TPA treatment induces ctsl mRNA in a manner that is dose-dependent, occurs at the level of transcription, and is ablated by cotreatment with cycloheximide but is unaffeded by dexamethasone. Treatment with TPA plus staurosporine, a potent protein kinase C inhibitor, results in greater expression of ctsl mRNA than does treatment with TPA alone. Similar to TPA, staurosporine alone increases ctsl transcription, an effed that is inhibited by cycloheximide. Another PKC inhibitor, H7, exerted no effed upon the indudion of ctsl mRNA by either TPA or staurosporine. Staurosporine and H7, however, inhibit the increase in c-jun mRNA by TPA. In contrast, the tyrosine kinase inhibitors herbimycin A and genistein inhibit the effed of TPA and staurosporine upon ctsl mRNA with little or no effed on c-jun expression. Pretreatment with sodium orthovanadate enhances the indudion of ctsl expression by TPA and staurosporine. These data suggest that, in U937 cells, TPA-stimulated ctsl gene transcription is apparently adivated by a protein kinase C-independent signal transdudion pathway involving tyrosine kinase adivation.