Erythropoietin and its mode of action.

Erythropoietin (Epo) is an unambiguous inducer of red cell differentiation in mammals. Purified Epo, derived from urine of anemic patients, is a glycoprotein of molecular weight about 34,000. There are two forms with the same biological activity and amino acid composition but with differing carbohydrate compositions. All of the carbohydrate is in the form of N-linked complex oligosaccharides. Erythropoietin appears to contain three domains, two protease-resistant regions containing all of the carbohydrate, connected by a protease-sensitive region containing the active site. Cells derived from mice infected with the anemia variant of the Friend leukemia, bind Epo specifically. The receptors have a dissociation constant of about 5 nM and there are only 600-700 per cell. Erythropoietin has a rapid effect on the transcription and processing of the globin genes. Among the enzymes of heme synthesis, it has an early effect only on uroporphyrinogen synthase. Studies with Epo and colony-stimulating factor (CSF) suggest that these inducers compete for the same, or very closely related cells of the hemopoietic system. When marrow cells are put into close apposition by centrifugation, their responses to Epo and CSF and the competitive actions of these inducers increase.