Erythropoietins: A common mechanism of action Steve Elliott, Elizabeth Pham, Iain C. Macdougall  Experimental Hematology  Volume 36, Issue 12, Pages 1573-1584 (December 2008) DOI: 10.1016/j.exphem.2008.08.003 Copyright © 2008 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 1 Erythropoiesis. BFUe=burst-forming unit–erythroid; CFUe=colony-forming unit–erythroid; Epo=erythropoietin; FLK=fetal liver kinase; FLT=fetal liver tyrosine kinase; G-CSF=granulocyte-colony stimulating factor; GEMM=granulocyte, erythrocyte, monocyte, megakaryocyte; GM-CSF=granulocyte macrophage CSF; IL=interleukin; MIP=macrophage inflammatory protein; SCF=stem cell factor; TGF=transforming growth factor; TPO=thrombopoietin. Experimental Hematology 2008 36, 1573-1584DOI: (10.1016/j.exphem.2008.08.003) Copyright © 2008 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 2 The nuclear magnetic resonance minimized average structure of human erythropoietin. Experimental Hematology 2008 36, 1573-1584DOI: (10.1016/j.exphem.2008.08.003) Copyright © 2008 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 3 Disproportion between half-life of recombinant human erythropoietin and lifespan of red blood cells. MEC=minimum effective dose. Adapted from Molineux [108] with permission. Experimental Hematology 2008 36, 1573-1584DOI: (10.1016/j.exphem.2008.08.003) Copyright © 2008 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 4 Signal transduction pathways of the erythropoietin receptor. Binding of erythropoietin (EPO) causes conformational changes to the EPO receptor, transphosphorylation of associated JAK2 molecules, phosphorylation of tyrosine residues in the cytoplasmic tail of the receptor, and phosphorylation or activation of signaling molecules. Phosphorylation of signal transducers and activators of transcription (STAT) 5 transcription factor (TF) causes homodimerization, translocation to the nucleus, and activation of genes for antiapoptotic molecules. Phosphorylated phosphatidylinositol 3-kinase (PI-3 kinase) phosphorylates protein kinase B (PKB)/Akt. PKB/Akt: 1) phosphorylates and inactivates proapoptotic molecules (Bad, caspase 9 or glycogen synthase kinase-3b [GSK-3b]); 2) phosphorylates FOXO TF, inhibiting translocation to the nucleus and activation of target genes (Fas ligand, Bim); and 3) phosphorylates IκB, allowing the release of the transcription factor nuclear factor (NF)-κB that then translocates into the nucleus and activates target genes encoding antiapoptotic molecules (XIAP, c-IAP2). Binding of EPO to its receptor also activates Hsp70, which binds to and inactivates proapoptotic molecules (apoptosis protease-activating factor-1 [Apaf-1], apoptosis-inducing factor [AIF]). Experimental Hematology 2008 36, 1573-1584DOI: (10.1016/j.exphem.2008.08.003) Copyright © 2008 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 5 Molecular structures of rhEPO (A) and darbepoetin alfa (B). Reprinted by permission from Macmillan Publishers Ltd: Nature Biotechnology [7], 2003. rhEPO=recombinant human erythropoietin. Experimental Hematology 2008 36, 1573-1584DOI: (10.1016/j.exphem.2008.08.003) Copyright © 2008 ISEH - Society for Hematology and Stem Cells Terms and Conditions