Phorbol ester stimulated cathepsin L expression in U937 cells.
Cathepsin L (ctsl) is a lysosomal cysteine proteinase, the synthesis and secretion of which is induced by transformation, growth factors, and tumor promoters. We studied the effect and the mechanism of action 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 unaffected 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 effect that is inhibited by cycloheximide. Another PKC inhibitor, H7, exerted no effect upon the induction 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 effect of TPA and staurosporine upon ctsl mRNA with little or no effect on c-jun expression. Pretreatment with sodium orthovanadate enhances the induction of ctsl expression by TPA and staurosporine. These data suggest that, in U937 cells, TPA-stimulated ctsl gene transcription is apparently activated by a protein kinase C-independent signal transduction pathway involving tyrosine kinase activation.
Atkins
K B
KB
Department of Internal Medicine, Veterans Administration Medical Center, University of Michigan, Ann Arbor 48109, USA.
Troen
B R
BR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D056668:Cathepsin L; D002403:Cathepsins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D004347:Drug Interactions; D010450:Endopeptidases; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology
D000470:Alkaloids; D007546:Isoquinolines; D009363:Neoplasm Proteins; D010879:Piperazines; D014638:Vanadates; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003513:Cycloheximide; D011493:Protein Kinase C; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate