Erythropoietins receptor

Phage display of random peptide libraries identified agonists of erythropoietin receptor... 

Figure 17.12 Ribbon diagram of EMPl bound to the extracellular domain of the erythropoietin receptor (EBP). Binding of EMPl causes dimerization of erythropoietin receptor. The x-ray crystal structure of the EMPl-EBP complex shows a nearly symmetrical dimer complex in which both peptide monomers interact with both copies of EBP. Recognition between the EMPl peptides and EBP utilizes more than 60% of the EMPl surface and four of six loops in the erythropoietin-binding pocket of EBP.

Macdougall IC (2005) CERA (Continuous Erythropoietin Receptor Activator) a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 4 436-440... 

EPA Eicosapentaenoic acid EpDIF Epithelial-derived inhibitory factor also known as epithelium/derived relaxant fector EPO Eosinophil peroxidase EPOR Erythropoietin receptor EPR Effector cell protease EPX Eosinophil protein X ER Endoplasmic reticulum ERCP Endoscopic retrograde cholangiopancreatography E-selectin Endothelial selectin formerly known as endothelial leucocyte adhesion molecule-1 (ELAM-1)... 

Pegzerepoetin alfa (also known as methoxy polyethylene glycol-epoetin beta) is a continuous erythropoietin-receptor activator that is licensed for... 

Gogu, S.R., Malter, J.S. and Agrawal, K.C. (1992) Zidovudine-induced blockade of the expression and function of the erythropoietin receptor. Biochemical Pharmacology, 44, 1009-1012. 

Erythropoietin stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors. The erythropoietin receptor is a member of the JAK/STAT superfamily of cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function (see Chapter 2). Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the... 

Epoetin alfa Agonist of erythropoietin receptors expressed by red cell progenitors Stimulates erythroid proliferation and differentiation, and induces the release of reticulocytes from the bone marrow Treatment of anemia, especially anemia associated with chronic renal failure, HIV infection, cancer, and prematurity prevention of the need for transfusion in patients undergoing certain types of elective surgery IV or SC administration 1-3 times per week Toxicity Hypertension, thrombotic complications, and, very rarely, pure red cell aplasia to reduce the risk of serious CV events, hemoglobin levels should be maintained < 12 g/dL... 

Predicting the Outcome of Phase I Studies of Erythropoietin Receptor Agonists... 

In this case study a simulation strategy, based on a mechanistic PK/PD model, was developed to predict the outcome of the first time in man (FTIM) and proof of concept (POC) study of a new erythropoietin receptor agonist (ERA). A description of the erythropoiesis model, along with the procedures to scale the pharmacokinetics and pharmacodynamics based on preclinical in vivo and in vitro information is presented. The Phase I study design is described and finally the model-based predictions are shown and discussed. 

Sinclair AM, Todd MD, Forsythe MD, Knox SJ, Elliott S, Begley CG. Expression and function of erythropoietin receptors in tumors implications for the use of erythropoiesis-stimulating agents in cancer patients. Cancer 2007 110 477-88. 

No rodent bioassay No tumorigenic or unexpected mitogenic response observed in any tissue type No binding to human tissues other than those expressing the erythropoietin receptor No alteration of proliferative response of non-hematological cells in vitro or in vivo Not genotoxic (Ames, in vitro chromosomal aberration, in vivo mouse MN)... 

Most of the control of tissue-specific gene expression occurs at the level of transcription this is achieved with tissue-specific transcription factors. For example, all genes that are to be expressed in erythroid cells, e.g., globin, spectrin, and erythropoietin receptor, have the site -AGATA- in their promoters. This site binds to a transcription factor (called GATA-l) which is present only in erythroid cells, and the promoter will function only in the presence of this factor. 

Constantinescu, S. N., Huang, L. J., Nam, H., and Lodish, H. F. (2001). The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol. Cell 7, 377-385. 

Wilson, I. A., and Jolliffe, L. K. (1999). The structure, organization, activation, and plasticity of the erythropoietin receptor. Cure. Opin. Struct. Biol. 9, 696-704. 

Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283(5404), 987-990. 

Remy, L, Wilson, I. A., and Michnick, S. W. (1999). Erythropoietin receptor activation by ligand-induced conformation change science. Science 283, 990-993. 

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