Biology Reference
In-Depth Information
[14, 17]. Other members of the cytokine receptor super-family have the poten-
tial to overcome the dominance of the EPOR in erythroid proliferation and dif-
ferentiation. Granulocyte colony-stimulating factor (G-CSF) induces
in vitro
the growth of erythroid colonies generated from G-CSF receptor overexpress-
ing hematopoietic cells derived from the fetal liver of EPOR
-/-
or STAT5a
-/-
mice (STAT = signal transducer and activator of transcription) [18].
These and other experiments give evidence that intact EPOR primarily
mediate the expansion of late BFU-E and CFU-E into mature red cells.
Approximately 300 EPOR are constitutively expressed on late BFU-E; recep-
tor numbers rise in CFU-E to approximately 1,100 per cell. EPOR density
remains high in erythroblasts, but EPORs are almost absent on reticulocytes
[19-21]. Furthermore, EPO stimulates the early release of maturing nor-
moblasts from their production site. The expression level of EPOR regulates
erythropoiesis by controlling the sensitivity of erythroid progenitor cells to
EPO [22]. EPO also increases the amount of hemoglobin synthesized per ery-
throcyte, and it suppresses programed erythroid cell death [23-25].
Molecular biology of the EPOR
Characteristics of the EPOR gene and structure of the EPOR
EPOR belongs to the cytokine receptor super-family, which is characterized by
a common domain structure, consisting of an extracellular ligand-binding
domain, a hydrophobic transmembrane domain, and an intracellular/cytoplas-
mic domain (Fig. 1) [26, 27]. The extracellular domain of members of the
cytokine receptor super-family is further characterized by four conserved cys-
teine residues and the WSXWS (tryptophan-serine-X (X = any amino acid)-
tryptophan-serine) motif. Also highly conserved are two motifs (box 1 and box
2) in the cytoplasmic domain [26]. The cytokine receptor super-family
includes receptors for various hematopoietic growth factors, e.g., G-CSF, gran-
ulocyte-macrophage colony-stimulating factor (GM-CSF), TPO, several inter-
leukins (including IL-2, -3, -4, -5, -6, -11, -15), growth hormone, prolactin,
and leptin among others [26, 28-31].
EPOR is highly conserved, and transgenic mice with homozygous EPOR
deletion can be rescued by the human
EPOR
gene [32]. In humans, the single
copy
EPOR
gene is localized on chromosome 19p, spans approximately 6 kb,
and contains eight exons. Exons 1-5 code for the extracellular domain, exon
6 for the transmembrane domain, and exons 7 and 8 for the intracellular
domain (Fig. 2) [4, 33].
Human EPOR is a cell surface protein which consists of 508 amino acids.
After a 24-amino acid leader sequence, the first 226 amino acids form the
extracellular domain; the transmembrane domain contains 23 amino acids, and
the intracellular domain has 235 amino acids. EPOR has a calculated molecu-
lar weight (MW) of approximately 55-56 Kd [5, 6, 33, 34]. Meanwhile mul-
