A bryostatin-sensitive protein kinase C required for nerve growth factor activity.
Nerve growth factor (NGF) stimulates rat pheochromocytoma cells (PC12) to differentiate into a neuronal-like cell that exhibits neurite extensions. The role of protein kinase C in signal transduction has been examined in PC12 cells treated with phorbol 12-myristate 13-acetate (PMA) and bryostatin, a macrocyclic lactone that activates protein kinase C at both the nuclear and the plasma membranes [Hocevar, B. A., & Fields, A. P. (1991) J. Biol. Chem. 266, 28-33]. In contrast to PMA down-regulation [Reinhold, D. S., & Neet, K. E. (1989) J. Biol. Chem. 264, 3538-3544], chronic (24 h) treatment with bryostatin blocked the formation of neurites in response to NGF or basic fibroblast-derived growth factor stimulation, but, like PMA, bryostatin did not block the induction of c-fos or c-jun protooncogenes by NGF. Chronic bryostatin treatment down-regulated protein kinase C activity in the cytosolic, membrane, and nuclear fractions. Acute (60 min) bryostatin or NGF treatment activated cytosolic and nuclear protein kinase C activity, suggesting possible translocation to the nucleus. Bryostatin did not induce neurite outgrowth, either alone or in combination with PMA. Thus, the bryostatin-sensitive protein kinase C is distinct from PMA- or K252a-sensitive kinases previously described. The bryostatin-sensitive protein kinase C is necessary, but not sufficient, for neurite outgrowth and acts in the nucleus in a manner independent of c-fos and c-jun transcription.
Singh
K R
KR
Department of Biological Chemistry, UHS/Chicago Medical School, Illinois 60064.
Taylor
L K
LK
Campbell
X Z
XZ
Fields
A P
AP
Neet
K E
KE
D000818:Animals; D054713:Bryostatins; D002454:Cell Differentiation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016762:Genes, fos; D016758:Genes, jun; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000648:ultrastructure; D016716:PC12 Cells; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D009414:Nerve Growth Factors; D012333:RNA, Messenger; C046785:bryostatin 1; D011493:Protein Kinase C; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate