Activation of two discrete signaling pathways by erythropoietin.
Erythropoietin stimulation of erythroid cells induces a rapid increase in c-myc and decrease in c-myb mRNA levels. The signal pathway to c-myc requires activation of protein kinase C. We now report that erythropoietin down-regulates expression of c-myb via a discrete, serine/threonine-specific phosphatase-dependent pathway. The protein kinase C-blocker H7 completely prevents the c-myc response to erythropoietin, but has no effect on the c-myb response. In contrast, the phosphatase blocker okadaic acid prevents the c-myb response but not the c-myc response. This effect of okadaic acid on the c-myb response is concentration-dependent. Both the protein kinase C-dependent signal to c-myc and the phosphatase-dependent signal to c-myb regulate gene expression by a transcriptional arrest mechanism operative within the first intron of the respective protooncogenes. In contrast, the chemical inducer of differentiation, dimethyl sulfoxide, regulates expression of c-myc and c-myb without activation of these phosphatase- and kinase-dependent pathways.
Patel
H R
HR
New England Deaconess Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215.
Choi
H S
HS
Sytkowski
A J
AJ
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D004921:Erythropoietin / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D007546:Isoquinolines; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D004921:Erythropoietin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases