TY - JOUR
T1 - Erythropoietin regulation of red blood cell production
T2 - From bench to bedside and back
AU - Weiss, Mitchell J.
AU - Bhoopalan, Senthil Velan
AU - Huang, Lily Jun shen
N1 - Funding Information:
Grant information: LJH is funded by National Institutes of Health (NIH) grant R01 HL089966. MJW is funded by NIH grants R01 DK61692
Publisher Copyright:
© 2020 Bhoopalan SV et al.
PY - 2020
Y1 - 2020
N2 - More than 50 years of efforts to identify the major cytokine responsible for red blood cell (RBC) production (erythropoiesis) led to the identification of erythropoietin (EPO) in 1977 and its receptor (EPOR) in 1989, followed by three decades of rich scientific discovery. We now know that an elaborate oxygen-sensing mechanism regulates the production of EPO, which in turn promotes the maturation and survival of erythroid progenitors. Engagement of the EPOR by EPO activates three interconnected signaling pathways that drive RBC production via diverse downstream effectors and simultaneously trigger negative feedback loops to suppress signaling activity. Together, the finely tuned mechanisms that drive endogenous EPO production and facilitate its downstream activities have evolved to maintain RBC levels in a narrow physiological range and to respond rapidly to erythropoietic stresses such as hypoxia or blood loss. Examination of these pathways has elucidated the genetics of numerous inherited and acquired disorders associated with deficient or excessive RBC production and generated valuable drugs to treat anemia, including recombinant human EPO and more recently the prolyl hydroxylase inhibitors, which act partly by stimulating endogenous EPO synthesis. Ongoing structure-function studies of the EPOR and its essential partner, tyrosine kinase JAK2, suggest that it may be possible to generate new 'designer' drugs that control selected subsets of cytokine receptor activities for therapeutic manipulation of hematopoiesis and treatment of blood cancers.
AB - More than 50 years of efforts to identify the major cytokine responsible for red blood cell (RBC) production (erythropoiesis) led to the identification of erythropoietin (EPO) in 1977 and its receptor (EPOR) in 1989, followed by three decades of rich scientific discovery. We now know that an elaborate oxygen-sensing mechanism regulates the production of EPO, which in turn promotes the maturation and survival of erythroid progenitors. Engagement of the EPOR by EPO activates three interconnected signaling pathways that drive RBC production via diverse downstream effectors and simultaneously trigger negative feedback loops to suppress signaling activity. Together, the finely tuned mechanisms that drive endogenous EPO production and facilitate its downstream activities have evolved to maintain RBC levels in a narrow physiological range and to respond rapidly to erythropoietic stresses such as hypoxia or blood loss. Examination of these pathways has elucidated the genetics of numerous inherited and acquired disorders associated with deficient or excessive RBC production and generated valuable drugs to treat anemia, including recombinant human EPO and more recently the prolyl hydroxylase inhibitors, which act partly by stimulating endogenous EPO synthesis. Ongoing structure-function studies of the EPOR and its essential partner, tyrosine kinase JAK2, suggest that it may be possible to generate new 'designer' drugs that control selected subsets of cytokine receptor activities for therapeutic manipulation of hematopoiesis and treatment of blood cancers.
KW - Erythropoiesis
KW - Erythropoietin receptor signaling
KW - Hypoxia-induced transcription factor
KW - JAK2
KW - Janus Kinase 2
KW - Prolyl hydroxylase inhibitor
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U2 - 10.12688/f1000research.26648.1
DO - 10.12688/f1000research.26648.1
M3 - Review article
C2 - 32983414
AN - SCOPUS:85091812085
SN - 2046-1402
VL - 9
JO - F1000Research
JF - F1000Research
M1 - 1153
ER -