H-89 inhibits collagenase induction by phorbol ester through a mechanism that does not involve protein kinase A.
Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) regulates the activity of growth-factor-induced pathways at the level of cytoplasmic kinases and nuclear transcription factors. We observed that H-89, an inhibitor of PKA, induced mitogen-activated protein (MAP) kinase activity in a 12V-ras-transformed fibroblast cell line. In contrast, H-89 inhibited phorbol-ester-mediated induction of MAP kinase, junB messenger ribonucleic acid (mRNA), and collagenase mRNA in these cells. Phorbol-ester stimulation of a collagenase-promoter reporter construct was also inhibited by H-89. However, stimulation of the collagenase promoter was not inhibited by overexpression of the PKA-inhibitory protein PKI. These data suggest that H-89 inhibits the activity of an enzyme required for phorbol-ester induction of collagenase mRNA, but that this inhibition does not occur at the level of PKA.
Shoshan
M C
MC
Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
Ljungdahl
S
S
Linder
S
S
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002461:Cell Line, Transformed; D017364:Collagenases / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D016758:Genes, jun; D007546:Isoquinolines / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D051381:Rats; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D007546:Isoquinolines; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017364:Collagenases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013755:Tetradecanoylphorbol Acetate