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J. Biol. Chem., Vol. 276, Issue 42, 38518-38526, October 19, 2001
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From the Laboratory for Cell and Molecular Biology, Division of
Hematology and Oncology, Beth Israel Deaconess Medical Center,
Department of Medicine, Harvard Medical School, Boston,
Massachusetts 02215
Erythropoietin (Epo) stimulation of
erythroid cells results in the activation of several kinases and a
rapid induction of c-myc expression. Protein kinase C is
necessary for Epo up-regulation of c-myc by promoting
elongation at the 3'-end of exon 1. PKC
Erythropoietin Activates Two Distinct Signaling Pathways Required
for the Initiation and the Elongation of c-myc*
mediates this signal. We now
show that Epo triggers two signaling pathways to c-myc. Epo
rapidly up-regulated Myc protein in BaF3-EpoR cells. The
phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 blocked Myc
up-regulation in a concentration-dependent manner but had
no effect on the Epo-induced phosphorylation of ERK1 and ERK2. LY294002
also had no effect on Epo up-regulation of c-fos. MEK1
inhibitor PD98059 blocked both the c-myc and the
c-fos responses to Epo. PD98059 and the PKC inhibitor H7
also blocked the phosphorylation of ERK1 and ERK2. PD98059 but not
LY294002 inhibited Epo induction of ERK1 and ERK2 phosphorylation in
normal erythroid cells. LY294002 blocked transcription of
c-myc at exon 1. PD98059 had no effect on transcription
from exon 1 but, rather, blocked Epo-induced c-myc
elongation at the 3'-end of exon 1. These results identify two Epo
signaling pathways to c-myc, one of which is
PI3K-dependent operating on transcriptional initiation,
whereas the other is mitogen-activated protein
kinase-dependent operating on elongation.
*
This work was supported by NASA Grants NAGW-4980 and
NAG8-1361 and National Institutes of Health Grant R01 CA89204 (to
A. J. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Tel.: 617-632-9980;
Fax: 617-632-0401; E-mail: asytkows@caregroup.harvard.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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