Inhibition of protein kinase C is associated with a decrease in c-myc expression in human myeloid leukemia cells.
Treatment of human myeloid leukemic cells with phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with activation and then partial down-regulation of protein kinase C activity. Previous work has suggested that the activation of protein kinase C by TPA contributes to the decrease in c-myc expression during differentiation of these cells. The present studies demonstrate that the decline in c-myc mRNA levels following exposure of HL-60 cells to TPA is preceded by an increase in expression of this gene. In contrast, exposure of HL-60 cells to inhibitors of protein kinase C activity is associated with down-modulation of c-myc expression. Similar findings have been obtained in U-937 myeloid leukemia cells. Taken together, these findings suggest that phorbol esters have a biphasic effect on c-myc expression. Whereas the activation of protein kinase C by phorbol esters may be associated with an increase in c-myc gene expression, the subsequent partial down-regulation of kinase activity may initiate a cascade of events resulting in the down-modulation of c-myc expression.
Bernstein
S H
SH
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Boston, MA.
Kharbanda
S M
SM
Sherman
M L
ML
Stone
R M
RM
Kufe
D W
DW
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D015152:Blotting, Northern; D002460:Cell Line; D004789:Enzyme Activation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D007951:Leukemia, Myeloid; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D019311:Staurosporine; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000470:Alkaloids; D007546:Isoquinolines; D010879:Piperazines; D011741:Pyrimidine Nucleosides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013449:Sulfonamides; C005699:sangivamycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate