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486 Part VI: The Erythrocyte Chapter 32: Erythropoiesis 487

play a physiologic role in many nonerythroid cells including endothe-
EPO EPOR signaling
113
lial cells, megakaryocytes, and cells of the brain, heart, uterus, breast,
and testis. However, in some tissues (e.g., brain, heart, and kidney) the
– + signaling mechanism may be different because EPO can interact with
EPOR and CD131 heterodimers. 114,115
Detrimental EPO effects include a poorly understood increased
JAK2 JAK2
cancer mortality, 95,116,117 increased blood pressure, and thrombosis. 114
STAT5
CIS Hypoxia-Inducible Factors
Under normal conditions, EPO production is mediated by decreased
HCP STAT5 STAT5 oxygen saturation of hemoglobin, that is, hypoxemia. Hypoxia is an
77
important factor in development, energy metabolism, vasculogene-
sis, iron metabolism, tumor promotion and is the principal regulator
PI3K of erythropoiesis. The response to hypoxia is controlled by transcrip-
Bcl-x L Proliferation
Prevention of apoptosis tional factors termed hypoxia-inducible factors (HIFs). 118,119 Adaptive
physiologic responses to hypoxia serve to (1) increase O delivery to
2
Figure 32–6. Outline of erythropoietin–erythropoietin receptor cells, (2) allow cells to survive under reduced O by activating glycol-
2
(EPO–EPOR) signaling. Activation of Janus kinase 2 (JAK2) and signal ysis, and (3) reduce the formation of reactive oxygen species. HIFs
120
transducer and activator of transcription 5 (STAT5) represents erythro- are heterodimeric transcription factors composed of a highly-regulated
poiesis-promoting signals. Interaction of CIS, a signal transduction
protein that downregulates activity of erythropoietin receptor, and α subunit and a constitutively expressed β subunit that belongs to the
hematopoietic cell phosphatase (HCP) inhibit erythropoiesis. Phosphat- basic helix-loop-helix containing the PER-ARNT-SIM (PAS)-domain
idylinositide 3′-kinase (PI3K) activation of Bcl-x inhibits apoptosis of ery- family of transcription factors. The first HIF to be discovered, HIF-1, is
L
throid progenitors. induced in hypoxic cells and binds to a cis-acting nucleotide sequence
of hypoxia-controlled genes referred to as the hypoxia-responsive
element, first identified in the 3′-flanking region of the human EPO
Nonerythroid Effect of Erythropoietin Signaling gene. Two other HIF homologues, HIF-2 and HIF-3, have been iden-
121
Soon after the erythroid effects of recombinant EPO were described, tified. HIF-2 has more limited tissue expression than HIF-1 but it is
nonerythroid effects were identified. Some of these effects are ben- the principal regulator of EPO expression. 118,119 Many hypoxia-inducible
111
eficial, including roles in neural, cardiovascular, and retinal tissues, genes are directly regulated by HIF-1. Approximately 3 percent of all
122
and in immune function and in tissue repair. It has been claimed that genes expressed in endothelial tissue are HIF-1 regulated. The half-
the hormone also exerts beneficial effects on athletic performance and life of HIF-1α in the cell is minutes under normoxic conditions. HIF-1
improved neurocognition, but these are not convincingly substanti- and HIF-2 α subunits are rapidly degraded by the von Hippel-Lindau
ated. The effects of EPO in nonerythroid tissues are the result of EPO (VHL) protein–ubiquitin–proteasome pathway. The targeting and
123
binding to EPOR, and, as in erythroid cells, the EPO–EPOR interac- subsequent polyubiquitination of HIF α subunits requires VHL, iron,
tion initiates a signal transduction process that regulates the survival, O , and proline hydroxylase activity, and this complex constitutes the
2
growth and differentiation of the involved tissue. EPO and EPOR oxygen sensor (Fig. 32-7). 124,125
112
Figure 32–7. Schematic outline of regulation
of HIF-2 and HIF-2α subunits by hypoxic and
nonhypoxic pathways. HIF, hypoxia-inducible
factor; HSP90, heat shock protein 90; PHDs,
proline hydroxylases; p300 and CBP, cofactors
of hypoxia response transcription with HIF-1;
RACK1, receptor of activated protein kinase C;
ub, ubiquitin residues; VHL, von Hippel-Lindau
protein.

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