Hematopoietic Factor Erythropoietin Fosters Neuroprotection through Novel Signal Transduction Cascades

Abstract

Summary:In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, erythropoietin and the erythropoietin receptor have recently been shown to modulate cellular signal transduction pathways that extend beyond the erythropoietic function of erythropoietin. In particular, erythropoietin has been linked to the prevention of programmed cell death in neuronal systems. Although this work is intriguing, the underlying molecular mechanisms that serve to mediate neuroprotection by erythropoietin are not well understood. Further analysis illustrates that erythropoietin modulates two distinct components of programmed cell death that involve the degradation of DNA and the externalization of cellular membrane phosphatidylserine residues. Initiation of the cascades that modulate protection by erythropoietin and its receptor may begin with the activation of the Janus tyrosine kinase 2 protein. Subsequent downstream mechanisms appear to lead to the activation of multiple signal transduction pathways that include transcription factor STAT5 (signal transducers and activators of transcription), Bcl-2, protein kinase B, cysteine proteases, mitogen-activated protein kinases, proteintyrosine phosphatases, and nuclear factor-B. New knowledge of the cellular pathways regulated by erythropoietin in neuronal environments will potentially solidify the development and initiation of therapeutic strategies against nervous system disorders.

Effect of haemopoietic growth factors on cancer cell lines and their role in chemosensitivity

“…Recent studies have shown that in addition to promoting the survival, proliferation and differentiation of immature erythroid cells through associations with the ERK pathway, Epo has been shown to modulate other MAPK and cellular signal transduction pathways (JNK and p38) (Silva et al, 1999;Kapur and Zhang, 2001;Chong et al, 2002). Indeed, it has been suggested that the ERK MAPK pathway may not be the principal mechanism of Epo activity (Kolonics et al, 2001).…”

Erythropoietin as an antiapoptotic, tissue-protective cytokine

“…60 The antiapoptotic action of NF-kB in neurons also involves activation of Akt1 and Bad phosphorylation 41,61 as well as Bcl-xL upregulation. 62,63 Bcl-xL was also found induced by EPO in a study where DNA microarrays were used to identify modulated genes in PC12 neuronal-like cells 64 and in vivo in a gerbil model of cerebral ischemia. 62 Of note, Ruscher et al, 61 studying the protective effect of EPO against oxygen glucose deprivation-induced apoptosis of primary cortical neurons, confirmed that the protective effect requires Jak2, as shown by Digicaylioglu and Lipton, 60 and of PI(3)Kinase, as shown by us, 39 using specific inhibitors of these kinases.…”

New Avenues of Exploration for Erythropoietin

“…2,4 Anemic stress, insulin release, and several cytokines, including insulinlike growth factor (IGF), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), also can lead to increased expression of EPO and the EPOR. [2][3][4] Several recent studies have outlined the mechanisms by which EPO may prevent cell injury (Figure). Protection by EPO in a number of cellular systems is robust and EPO prevents apoptosis from a number of sources, including reduced or absent oxygen tension, excitotoxicity, and free radical exposure.…”