Ira Astuti Hasibuan

POSTGRADUATE BIOMEDICAL SCIENCE

FACULTY OF MEDICINE
UNIVERSITY SUMATERA UTARA

Erythropoietin ( EPO ) is growth factor that promotes

the viability, proliferation and differentiation of
mammalian erythroid progenitor.

Epo binds to the Epo receptor (EpoR) expressed

progenitor cells in bone marrow

EPO signals

via two receptors, one comprising EPO

receptor (EPOR) homodimers and the other a
heterodimer of EPOR and CD131the common
chain component of the GM-CSF, interleukin (IL)-3,
and IL-5 receptors.

 In contrast to many other

hematopoietic
growth
factors, EPO primarily
affects relatively mature
erythroid cells, although it
may also influence the
growth and behavior of
other cells.
EPO-induced
intracellular signaling in
erythroid progenitor and
precursor cells is mediated
via EPOR
homodimerization .

NONERYTHROPOIETIC ACTIONS OF EPO IN NUMEROUS TISSUE

Glicoprotein, BM 30 kDa, 165

amino acid, 4 glican

Produced by cortical
nepron mainly in the
intercalated cells in
normal hematopoietic
condition and by
mainly peritubular
cells in hypoxia

EPO

Fetus liver

Its synthese is regulated in

transkripsional level.

mRNA EPO is
also detected in :
brain,liver,lymph,
testis

EPO gene expression is

induced by hypoxia-inducible
transcription factors ( HIF )
HIF-1 composed of an O2labile- subunit and a
constant nuclear subunit.
In hypoxia, HIF-1 enters
the nucleus to form the active
transcription complex with
p300/CREB and HIF-1.

O2 capacity decrease
Induction of
EPO gene
expression

Arterial pressure decrease

Plasma O2 affinity increase

MOLECULAR ACTION OF ERYTHROPOIETIN

Sumber : The potential of erythropoietin to treat asphyxia in newborns.

Gillian C Pet, Sandra E Juul.Department of Pediatrics, Division of
Neonatology, University of Washington, Seattle, WA, USA

EPO RECEPTOR

Gastric
mucose ,
enterocyte

endothel,
smooth
muscle,
cardiac
muscle
Cardio
vaskular

ENDOCRYNE
SYSTEM

Langerhans
island cell ,
parathyroid
cell, pituitary
gland

DIGESTIVE
TRACT

REPRODUCTIVE

SYSTEM

Male : testis, leydig cell

Female : vaskular
endothel and smooth
muscle, decidua of
endometrium,,glandular
,epithelial cell,fovarium
folicle

NEGATIVE REGULATION OF EPO-R

SIGNALLING
EPO-R signalling is terminated as a result of the
interaction of certain protein with the EPO-R or with
signalling molecules.Among these proteins a major player
is :
SHPI, which is recruited via its SH2 domains to P-Tyr
429 of the EPO-R leading to dephosphorylation of JAK2
and down-regulation of positive signals.
CIS proteinfamily, known as :
SOCS ( supressor of cytokine signalling ) or SSI ( STATinduced STAT inhibitor )
JAB ( JAK binding independently )
SOCS1
SSII

CLINICAL DISORDER OF EPO-R

Polycithemia

Neoplastic
disorder

Solid
malignancies

Low serum EPO characterises primary familial and

congenital policythemia
Secondary familial policythemia is associated with
high serum EPO and intact EPO-R signalling
The exprssion of EPO-R has been observed in all
subtypes of acute myeloid leukemia according to the
FAB.
Expression of EPO also observed in 29 % patients
withacute lymphoblastic leukemia
EPO and EPO-R expression are observed in breast
carcinoma samples and tumor vasculature compared
to benign changes or normal tissue
Expression of EPO and EPO-R is highest in hypoxic
tumor regions

RECOMBINANT HUMAN EPO ( rHuEPO )

Therapy with recombinant human EPO has become a
standard for correction of renal and non renal
anemias.
Potential non-renal indications for rHuEPO
administration include the anemia associated with
cancer, autoimmune diseases, AIDS, bone marrow
transplantation and myelodysplastic syndrome.
In tumor patients rHuEPO therapy aims at

maintaining patients hemoglobin values above the

transfusion trigger, increasing the exercise tolerance
and improving quality of life parameters.

CURRENT AND POTENTIAL FUTURE USES OF RECOMBINANT EPO AND

ITS DERIVATIVES IN CLINICAL PRACTICE

SUMMARY
Erythropoietin is a hormone produced by renal and has its
action in bone marrow to prevent apoptosis of CFUerythroblast ,therefore the mature erythrosit is produced.
EPO receptor is also found in another organ such as in
endothel vascular, gastric mucosa, endocrine cell and testis,
which play non-erythrocyte action.
EPO recombinant has become standard therapy for
anemia caused by renal or non-renal disease and has
potential uses in future.

REFERENCES
Jelkmann W. 2004. Molecular Biology of Erythropoietin. Internal
Medicine Vol 43, No.8
Cohen J., Supino-Rosin L., Barzilay E., 2002. Erythropoietin and Its
Receptor Signalling and Clinical Manifestations., IMAJ Vol.4: 1072-1076
Broxmeyer H., 2013. Erythropoietin : multiple targets, actions, and
modifying influences for biological and clinical consideration. J Exp
Med Vol 210 No.2. 205-208
Arcasoy M. 2008. The non-haematopoietic biological effects of
erythropoietin. British Journal of Haematology. 141, 14-31
Youssoufian H., Longmore G., Neumann D. 2016. Structure,
Function, and Activation of the Erythropoietin Receptor. Blood Journal
Vol.81, No.9

THANK YOU