K-252a inhibits the increase in c-fos transcription and the increase in intracellular calcium produced by nerve growth factor in PC12 cells.
K-252a, a kinase inhibitor isolated from the culture broth of Nocardiopsis sp., selectively inhibits, in a dose- and time-dependent fashion, the increased transcription of the protooncogene c-fos induced by nerve growth factor in PC12 cells. Induction of c-fos by epidermal growth factor, A23187, dBcAMP, or TPA in the same cells is not affected. Pretreatment with K-252a for 30 min results in a complete inhibition of the nerve growth factor-induced increase in intracellular calcium. Increases in intracellular calcium induced by carbachol or by high K+ are not altered. K-252a derivatives selective for the inhibition of various known kinases were used to inhibit the nerve growth factor-dependent induction of c-fos mRNA, the nerve growth factor-dependent increase in intracellular calcium levels, and the nerve growth factor-dependent outgrowth of neurites. K-252a is the most effective inhibitor of all three of these actions of nerve growth factor. The possible mechanisms by which K-252a acts on PC12 cells are considered in the light of the characteristics of the inhibitions seen here.
Lazarovici
P
P
Section on Growth Factors, National Institute of Child Health and Human Development, Bethesda, Maryland.
Levi
B Z
BZ
Lelkes
P I
PI
Koizumi
S
S
Fujita
K
K
Matsuda
Y
Y
Ozato
K
K
Guroff
G
G
D000310:Adrenal Gland Neoplasms; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D026121:Indole Alkaloids; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009693:Nucleic Acid Hybridization; D010673:Pheochromocytoma; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D011519:Proto-Oncogenes / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D014158:Transcription, Genetic / Q000187:drug effects*
D002227:Carbazoles; D004268:DNA-Binding Proteins; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C049985:staurosporine aglycone; D011493:Protein Kinase C; D002118:Calcium