Biology Reference
In-Depth Information
A.
I
II
III IV
VVI
VII VIII
5'
3'
TAG
ATG
B.
+
1
-1050
-450
+78 +135
5'
3'
Alu
repetitive elements
-76
+33
ATG
minimal
promoter
C.
5'
••••••••••••
ccgcc
••••••
tatc
•••••••••••••••••
ccgcc
••••••••••••
act
••••••••••••••••••••••••
3'
-76
+33
Sp1
Sp1
GATA-1
Figure 2. Genomic organization of human
EPOR
gene. Panel A shows the organization of the entire
gene locus. In Panel B, the minimal promoter of
EPOR
gene is indicated by scattered lines. A posi-
tive regulatory domain (open box) from nt+1 to +78 contains potential binding sites for proteins of
the helix-loop-helix family. Negative regulatory domains are indicated by filled boxes. Panel C refers
to important binding sites in the minimal promoter region and the transcription start site (arrow).
motifs. Box 1 (residues 257-264) and box 2 (residues 303-309) subdomains
together with a tyrosine site 343 (Fig. 1) are required for initiation of signal-
ing cascades and further for the development of committed progenitor cells
within both the erythroid and the megakaryocytic lineage [40, 41]. A region
between box 1 and box 2 (residues 267-276) also plays a role in EPOR inter-
nalization [42, 43]. The distal region of the intracellular domain, encoded by
exon 8, acts as a negative regulatory domain, where proteins bind that deter-
mine the signaling process [44]. Accordingly, the activation of the seven tyro-
sine residues (Y401 to Y479, Fig. 2) is not required for the growth and termi-
nal differentiation of erythroid progenitors [45]. However, the distal cytoplas-
mic domain of EPOR can also induce a specific myeloid differentiation signal
distinct from mitogenic signaling as shown in murine 32D cells, transfected
with truncated EPOR [46].
Activation of EPOR, induction, and termination of signaling
Different mechanisms are identified for the binding of the ligand to the extra-
cellular domain of EPOR. Usually, one EPO molecule binds to two EPOR and
