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Erythropoietin: new directions for the nervous system.

Maiese K, Chong ZZ, Shang YC, Wang S - Int J Mol Sci (2012)

Bottom Line: EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease.Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders.Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular and Molecular Signaling, Cancer Center, F 1220, New Jersey Health Sciences University, 205 South Orange Avenue, Newark, NJ 07101, USA; E-Mails: zzchong@yahoo.com (Z.Z.C.); ycshang2000@yahoo.com (Y.C.S.); wsh2078@gmail.com (S.W.) ; Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA ; New Jersey Health Sciences University, Newark, New Jersey 07101, USA.

ABSTRACT
New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control β-catenin, glycogen synthase kinase-3β, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.

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Related in: MedlinePlus

Erythropoietin (EPO) employs novel signaling pathways to prevent apoptotic cell death. EPO can stimulate the phosphoinositide-3-kinase (PI 3-K) and subsequently lead to the activation of Akt. Akt can phosphorylate the forkhead transcription factor FoxO3a to prevent its nuclear translocation and transcription of “pro-apoptotic” genes. EPO through Wnt1 phosphorylates Akt and glycogen synthase kinase-3β (GSK-3β) to prevent β-catenin phosphorylation by GSK-3β and promote the nuclear translocation of β-catenin to increase transcription of “anti-apoptotic genes”. Phosphorylated FoxO3a and β-catenin are recruited and bound by cytoplasmic docking protein 14-3-3. In addition, EPO also integrates Wnt1 to regulate the expression of X-linked inhibitor of apoptosis protein (XIAP), anti-apoptotic protein Bcl-xL, and apoptotic protease activating factor-1 (Apaf-1). These processes prevent caspase activation and the induction of apoptosis. Mammalian target of rapamycin (mTOR) is another target for EPO to prevent apoptosis. Following activation of mTOR, p70 ribosomal S6 kinase (p70S6K) is phosphorylated and activated. The activated p70S6K increases the expression of Bcl-2/Bcl-xL, phosphorylates Bad, and results in the dissociation of Bad with Bcl-2/Bcl-xL. This leads to an increase in the binding of Bad to the protein 14-3-3 and more available Bcl-2/Bcl-xL to prevent apoptosis.
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f1-ijms-13-11102: Erythropoietin (EPO) employs novel signaling pathways to prevent apoptotic cell death. EPO can stimulate the phosphoinositide-3-kinase (PI 3-K) and subsequently lead to the activation of Akt. Akt can phosphorylate the forkhead transcription factor FoxO3a to prevent its nuclear translocation and transcription of “pro-apoptotic” genes. EPO through Wnt1 phosphorylates Akt and glycogen synthase kinase-3β (GSK-3β) to prevent β-catenin phosphorylation by GSK-3β and promote the nuclear translocation of β-catenin to increase transcription of “anti-apoptotic genes”. Phosphorylated FoxO3a and β-catenin are recruited and bound by cytoplasmic docking protein 14-3-3. In addition, EPO also integrates Wnt1 to regulate the expression of X-linked inhibitor of apoptosis protein (XIAP), anti-apoptotic protein Bcl-xL, and apoptotic protease activating factor-1 (Apaf-1). These processes prevent caspase activation and the induction of apoptosis. Mammalian target of rapamycin (mTOR) is another target for EPO to prevent apoptosis. Following activation of mTOR, p70 ribosomal S6 kinase (p70S6K) is phosphorylated and activated. The activated p70S6K increases the expression of Bcl-2/Bcl-xL, phosphorylates Bad, and results in the dissociation of Bad with Bcl-2/Bcl-xL. This leads to an increase in the binding of Bad to the protein 14-3-3 and more available Bcl-2/Bcl-xL to prevent apoptosis.

Mentions: EPO uses Wnt1 and its signaling pathways such as β-catenin to prevent apoptotic cell injury. In models of experimental diabetes, EPO preserves brain EC integrity that is necessary for protection of the neurovascular unit through Wnt1, since administration of anti-Wnt1 neutralizing antibodies or gene silencing of Wnt1 block EPO protection (Figure 1) [68,71]. EPO also uses Wnt1 to maintain and translocate β-catenin to the cell nucleus to initiate “anti-apoptotic” pathways and also prevent activation of the “pro-apoptotic” pathways of glycogen synthase kinase-3β (GSK-3β) [68]. EPO also has been shown to improve Wnt family signaling in mesenchymal stem cells and increase their resistance against a neurotoxic environment [188]. Wnt1 can modulate Apaf-1 and X-linked inhibitor of apoptosis protein (XIAP) through EPO to maintain microglial cell survival during oxygen-glucose deprivation (OGD) [78]. In addition, the potential protective capacity of EPO and Wnt1 during Alzheimer’s disease may be linked to the ability of EPO and Wnt1 to govern Bad, Bcl-xL, and caspase activity and increase microglial cell survival during Aβ toxicity [79].


Erythropoietin: new directions for the nervous system.

Maiese K, Chong ZZ, Shang YC, Wang S - Int J Mol Sci (2012)

Erythropoietin (EPO) employs novel signaling pathways to prevent apoptotic cell death. EPO can stimulate the phosphoinositide-3-kinase (PI 3-K) and subsequently lead to the activation of Akt. Akt can phosphorylate the forkhead transcription factor FoxO3a to prevent its nuclear translocation and transcription of “pro-apoptotic” genes. EPO through Wnt1 phosphorylates Akt and glycogen synthase kinase-3β (GSK-3β) to prevent β-catenin phosphorylation by GSK-3β and promote the nuclear translocation of β-catenin to increase transcription of “anti-apoptotic genes”. Phosphorylated FoxO3a and β-catenin are recruited and bound by cytoplasmic docking protein 14-3-3. In addition, EPO also integrates Wnt1 to regulate the expression of X-linked inhibitor of apoptosis protein (XIAP), anti-apoptotic protein Bcl-xL, and apoptotic protease activating factor-1 (Apaf-1). These processes prevent caspase activation and the induction of apoptosis. Mammalian target of rapamycin (mTOR) is another target for EPO to prevent apoptosis. Following activation of mTOR, p70 ribosomal S6 kinase (p70S6K) is phosphorylated and activated. The activated p70S6K increases the expression of Bcl-2/Bcl-xL, phosphorylates Bad, and results in the dissociation of Bad with Bcl-2/Bcl-xL. This leads to an increase in the binding of Bad to the protein 14-3-3 and more available Bcl-2/Bcl-xL to prevent apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472733&req=5

f1-ijms-13-11102: Erythropoietin (EPO) employs novel signaling pathways to prevent apoptotic cell death. EPO can stimulate the phosphoinositide-3-kinase (PI 3-K) and subsequently lead to the activation of Akt. Akt can phosphorylate the forkhead transcription factor FoxO3a to prevent its nuclear translocation and transcription of “pro-apoptotic” genes. EPO through Wnt1 phosphorylates Akt and glycogen synthase kinase-3β (GSK-3β) to prevent β-catenin phosphorylation by GSK-3β and promote the nuclear translocation of β-catenin to increase transcription of “anti-apoptotic genes”. Phosphorylated FoxO3a and β-catenin are recruited and bound by cytoplasmic docking protein 14-3-3. In addition, EPO also integrates Wnt1 to regulate the expression of X-linked inhibitor of apoptosis protein (XIAP), anti-apoptotic protein Bcl-xL, and apoptotic protease activating factor-1 (Apaf-1). These processes prevent caspase activation and the induction of apoptosis. Mammalian target of rapamycin (mTOR) is another target for EPO to prevent apoptosis. Following activation of mTOR, p70 ribosomal S6 kinase (p70S6K) is phosphorylated and activated. The activated p70S6K increases the expression of Bcl-2/Bcl-xL, phosphorylates Bad, and results in the dissociation of Bad with Bcl-2/Bcl-xL. This leads to an increase in the binding of Bad to the protein 14-3-3 and more available Bcl-2/Bcl-xL to prevent apoptosis.
Mentions: EPO uses Wnt1 and its signaling pathways such as β-catenin to prevent apoptotic cell injury. In models of experimental diabetes, EPO preserves brain EC integrity that is necessary for protection of the neurovascular unit through Wnt1, since administration of anti-Wnt1 neutralizing antibodies or gene silencing of Wnt1 block EPO protection (Figure 1) [68,71]. EPO also uses Wnt1 to maintain and translocate β-catenin to the cell nucleus to initiate “anti-apoptotic” pathways and also prevent activation of the “pro-apoptotic” pathways of glycogen synthase kinase-3β (GSK-3β) [68]. EPO also has been shown to improve Wnt family signaling in mesenchymal stem cells and increase their resistance against a neurotoxic environment [188]. Wnt1 can modulate Apaf-1 and X-linked inhibitor of apoptosis protein (XIAP) through EPO to maintain microglial cell survival during oxygen-glucose deprivation (OGD) [78]. In addition, the potential protective capacity of EPO and Wnt1 during Alzheimer’s disease may be linked to the ability of EPO and Wnt1 to govern Bad, Bcl-xL, and caspase activity and increase microglial cell survival during Aβ toxicity [79].

Bottom Line: EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease.Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders.Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular and Molecular Signaling, Cancer Center, F 1220, New Jersey Health Sciences University, 205 South Orange Avenue, Newark, NJ 07101, USA; E-Mails: zzchong@yahoo.com (Z.Z.C.); ycshang2000@yahoo.com (Y.C.S.); wsh2078@gmail.com (S.W.) ; Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA ; New Jersey Health Sciences University, Newark, New Jersey 07101, USA.

ABSTRACT
New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control β-catenin, glycogen synthase kinase-3β, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.

Show MeSH
Related in: MedlinePlus