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effects on Epo expression. The GATA site preferentially binds the
transcription factor GATA-2, which has been reported to inhibit
Epo gene expression (
34, 35
). NFkB binding to a site adjacent to
the minimal HRE of the Epo promoter also inhibits Epo expression.
Although activities of GATA-2 and NFkB in HepG2 cells decrease
in hypoxia compared to normoxia conditions both transcription
factors were shown to be involved in the suppression of Epo gene
expression by IL-1b and TNFa (
35
). Thus these pathways may
be responsible for impaired Epo synthesis in a variety of
inflammatory diseases and cancers.
2
EpoR Is Expressed in Multiple Tissues
Hypoxia and anemia are major events known to induce Epo gene
expression, however it should be noted that many different injuries
induce Epo expression (
36, 37
). Once the signals are transduced
erythropoietin is released into the circulating blood flow and finally
binds cells expressing the Epo receptor (EpoR).
The EpoR is a member of the type 1 superfamily of single-
transmembrane cytokine receptors (
38, 39
). Expression of the
EpoR is located in progenitor cells from hematopoietic, endothe-
lial, skeletal muscle, and neuronal compartments (
40-42
). EpoR is
downregulated during differentiation of erythroid cells and not
expressed on skeletal muscle. Interestingly, despite being significantly
downregulated in developing neuronal tissues until embryonic day
17, EpoR expression persists in select vascular and neuronal com-
partments. EpoR has been observed in brain during development
and adulthood (
37, 43-46
). More recent studies have demonstrated
expression of EpoR on cells from a variety of tissues including heart
(
47
), kidney (
48
), pancreas (
49
), and uterus (
50
).
3
Classical Erythroid EpoR Signaling
Erythropoiesis is stimulated by generating a complex network of
molecular signals involved in the control of cell proliferation, differ-
entiation, and death. EpoR homodimers are expressed on the eryth-
roid progenitor cell surface (
51
) and binding of Epo to the EpoR
triggers conformational changes in the receptor extracellular domain
that consequently activates JAK2 by autophosphorylation (
52, 53
).
JAK2 activation results in the phosphorylation of tyrosine residues on
the cytoplasmic region of EpoR and recruits a variety of Src homol-
ogy-2 (SH2) domain-containing proteins that initiate downstream
cascades via different signaling pathways including signal transducer
and activator of transcription (STAT), phosphatidylinositol-3 kinase
(PI3K)/Akt (also known as protein kinase B) and mitogen-activated
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