NGF-induction of the metalloproteinase-transin/stromelysin in PC12 cells: involvement of multiple protein kinases.
In previous work, we found that nerve growth factor (NGF) induced expression of the mRNA transcript encoding the metalloproteinase transin/stromelysin in PC12 cells. Transin was found, moreover, to be a "late" gene product whose expression correlated with neurites extension. In this study, various aspects of the NGF intracellular signaling pathway in PC12 cells are investigated. We show that the protein kinase inhibitor staurosporine, but not various other kinase inhibitors, specifically blocked the NGF induction of transin. Preliminary characterization of this staurosporine-sensitive kinase suggest that it does not correspond to a tyrosine kinase, nor various serine kinases, and that it is involved both at the transcriptional and posttranscriptional levels of transin gene regulation. In contrast to these effects of staurosporine, various activators of protein kinases C and A augmented the NGF induction of transin. Similar effects of these kinase inhibitors and activators were also observed with the expression of various immediate-early genes that have been proposed to mediate the transcriptional effects of NGF, including c-fos and c-jun. These data suggest, therefore, that the NGF induction of transin mRNA expression involves multiple protein kinases acting at a number of postreceptor regulatory steps in the NGF signaling pathway.
Machida
C M
CM
Department of Cell Biology and Anatomy, Oregon Health Sciences University, Portland 97201-3098.
Scott
J D
JD
Ciment
G
G
D000310:Adrenal Gland Neoplasms; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D007381:Intermediate Filament Proteins / Q000235:genetics; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016900:Neurofilament Proteins; D010673:Pheochromocytoma; D011493:Protein Kinase C / Q000502:physiology; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D004268:DNA-Binding Proteins; D007381:Intermediate Filament Proteins; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014157:Transcription Factors; D011493:Protein Kinase C; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate