Erythropoietin

Abstract

During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.

Protein Kinase C (PKC) Isozymes and Cancer

“…TPA-induced growth arrest in the G 0 /G 1 phase, upregulation of cancer suppressor gene miR-101, and downregulation of enhancer of zeste homolog 2 during embryonic ectoderm development in HepG2 cells are all PKC -dependent [274]. Downregulation of PKC by adding TPA into Hep3B cells also decreases the production of erythropoietin [263], which is a glycoprotein hormone that is stimulated under the hypoxic environment [275]. On the other hand, expression of PKC and suppresses HGFinduced phosphorylation of ERK and paxillin, resulting in the reduction of HepG2 cell migration, whereas PKC and are required for phosphorylation of paxillin [276].…”

Mechanism of Erythropoietin Regulation by Angiotensin II

“…Activation of GATA-2 and nuclear factor-kB in response to inflammatory cytokines interleukin-1b and tumor necrosis factor-a suppress EPO expression in cell culture (La Ferla et al, 2002). Other factors, including insulin, estrogen, androgens, and prostaglandin, modulate EPO production, although the mechanisms of EPO regulation by these factors are unknown (Ebert and Bunn, 1999;Hardee et al, 2006;Bunn, 2013). Importantly, despite the clinical importance of EPO for patient treatment, the mechanism(s) for basal regulation of EPO expression in the kidney is not well understood.…”

“…Under hypoxic conditions, hypoxia-inducible factors (HIFs) are the essential transcriptional regulators of the hypoxia response element of the EPO gene promoter (Eckardt and Kurtz, 2005;Jelkmann, 2007). Evidence indicates that HIF-2a protein, and not HIF-1a, is required for hypoxiainduced expression of EPO in the kidney, in EPO-producing cultured renal cells, and in the fetal liver (Rosenberger et al, 2002;Warnecke et al, 2004;Bunn, 2013). In contrast, GATA transcription factors (GATA-1, -2, and -3) and nuclear factor-kB negatively regulate EPO gene transcription (Imagawa et al, 1997;La Ferla et al, 2002;Obara et al, 2008).…”

Erythropoietin: friend and foe!

“…Indeed, while these studies assumed that the effects of (rHu)Epo are secondary to activation of gene expression, it now appears that Epo could also mitigate the acute inflammatory response thanks to its antioxidant properties. Bunn (2013) recently published a comprehensive review on the effects of Epo in which he highlighted that it confers protection against cardiac hypoxia/ ischaemia and myocardium infract, and help preserving kidney or liver integrity. During ischaemia and inflammation, Epo seems to exert its protective effects by stimulating the proliferation, mobilization and differentiation of endothelial cells, by enhancing endothelial cell viability and by reducing apoptosis.…”