PHORBOL ESTER-STIMULATED CATHEPSIN-L EXPRESSION IN U937 CELLS

Cathepsin L (ctsl) is a lysosomal cysteine proteinase, the synthesis a nd secretion of which is induced by transformation, growth factors, an d tumor promoters. We studied the effect and the mechanism of action o f phorbol ester (TPA) on the expression of cfsl mRNA in U937 histiocyt ic 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 unaffected by dexamethasone. Treatment with TPA plus staurosporine, a potent protein kinase C inhib itor, results in greater expression of cfsl mRNA than does treatment w ith TPA alone. Similar to TPA, staurosporine alone increases ctsl tran scription, an effect that is inhibited by cycloheximide. Another PKC i nhibitor, H7, exerted no effect upon the induction of cfsl mRNA by eit her TPA or staurosporine. Staurosporine and H7, however, inhibit the i ncrease in c-jun mRNA by TPA. In contrast, the tyrosine kinase inhibit ors herbimycin A and genistein inhibit the effect of TPA and staurospo rine upon ctsl mRNA with little or no effect on c-jun expression. Pret reatment with sodium orthovanadate enhances the induction of cfsl expr ession by TPA and staurosporine. These data suggest that, in U937 cell s, TPA-stimulated cfsl gene transcription is apparently activated by a protein kinase C-independent signal transduction pathway involving ty rosine kinase activation.