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.