Molecular biology of erythropoietin.
The glycoprotein hormone erythropoietin (EPO) is an essential viability and growth factor for the erythrocytic progenitors. EPO is mainly produced in the kidneys. EPO gene expression is induced by hypoxia-inducible transcription factors (HIF). The principal representative of the HIF-family (HIF-1, -2 and -3) is HIF-1, which is composed of an O2-labile alpha-subunit and a constant nuclear beta-subunit. In normoxia, the alpha-subunit of HIF is inactivated following prolyl- and asparaginyl-hydroxylation by means of alpha-oxoglutarate and Fe(2+)-dependent HIF specific dioxygenases. While HIF-1 and HIF-2 activate the EPO gene, HIF-3, GATA-2 and NFkappaB are likely inhibitors of EPO gene transcription. EPO signalling involves tyrosine phosphorylation of the homodimeric EPO receptor and subsequent activation of intracellular antiapoptotic proteins, kinases and transcription factors. Lack of EPO leads to anemia. Treatment with recombinant human EPO (rHuEPO) is efficient and safe in improving the management of the anemia associated with chronic renal failure. RHuEPO analogues with prolonged survival in circulation have been developed. Whether the recent demonstration of EPO receptors in various non-hemopoietic tissues, including tumor cells, is welcome or ominous still needs to be clarified. Evidence suggests that rHuEPO may be a useful neuroprotective agent.
Institute of Physiology, University of Luebeck, Luebeck, Germany.
Wolfgang
W
Jelkmann
D000740:Anemia / Q000188:drug therapy; D004268:DNA-Binding Proteins / Q000502:physiology; D004921:Erythropoietin / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000235:genetics; D006397:Hematinics / Q000627:therapeutic use; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000502:physiology; D011994:Recombinant Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D006397:Hematinics; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D004921:Erythropoietin