Induction of the collagenase phorbol ester response element by staurosporine.
The indol alkaloid staurosporine is a potent inhibitor of protein kinase C, but has also been shown to have certain effects paradoxically similar to those of protein kinase C-activating phorbol esters. We show here that collagenase mRNA expression is stimulated by 10 nM staurosporine in normal and ras-oncogene-transformed rat fibroblasts. The kinetics of collagenase mRNA induction by staurosporine were slow compared to induction by phorbol ester. Staurosporine induction of the collagenase promoter appeared to be mediated via the TPA response element (TRE). Induction did not involve any increase in jun mRNA expression and did not require expression of c-Jun. Prolonged treatment with phorbol ester to deplete protein kinase C did not inhibit stimulation of the collagenase promoter by staurosporine. Instead, involvement of cAMP-dependent protein kinase (PKA) was indicated by inhibition of staurosporine induction by the PKA inhibitor H-89. In addition, raised levels of cAMP were observed during the first hour of staurosporine treatment. Altogether, our data indicate that staurosporine induces a PKA-dependent pathway leading to c-Jun-independent activation of the collagenase TRE element.
Department of General Oncology, Radiumhemmet, Karolinska Institute and Hospital, Stockholm, Sweden.
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D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D003094:Collagen / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004492:Edetic Acid / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D016758:Genes, jun; D011905:Genes, ras; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D016759:Oncogene Protein p65(gag-jun) / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D019311:Staurosporine; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000470:Alkaloids; D007546:Isoquinolines; D016759:Oncogene Protein p65(gag-jun); D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013449:Sulfonamides; D003094:Collagen; D004492:Edetic Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019311:Staurosporine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013755:Tetradecanoylphorbol Acetate