Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative

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It is now recognized that in addition to its activity upon erythroid progenitor cells, erythropoietin (Epo) is capable of stimulating survival of different non-erythroid cells. Since stimulation of erythropoiesis is unwanted for neuroprotection, Epo-like compounds with a more selective action are un...

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Autores principales:	Chamorro, M.E., Wenker, S.D., Vota, D.M., Vittori, D.C., Nesse, A.B.
Formato:	Artículo publishedVersion
Lenguaje:	Inglés
Publicado:	2013
Materias:	Carbamylated erythropoietin Cell cycle Cell proliferation Erythropoietin FOXO3a P27kip1 carbamylated derivative of erythropoietin cyclin dependent kinase inhibitor 1B erythropoietin transcription factor FKHRL1 unclassified drug apoptosis article cell cycle G1 phase cell cycle progression cell cycle S phase cell differentiation cell proliferation controlled study human human cell neuroblastoma cell priority journal protein expression protein phosphorylation signal transduction Apoptosis Cell Differentiation Cell Growth Processes Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p27 Erythroid Cells Erythropoiesis Forkhead Transcription Factors G1 Phase Humans Neurons Phosphorylation Receptors, Erythropoietin S Phase Signal Transduction
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_01674889_v1833_n8_p1960_Chamorro
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paperaa:paper_01674889_v1833_n8_p1960_Chamorro
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spelling	paperaa:paper_01674889_v1833_n8_p1960_Chamorro2023-06-12T16:46:59Z Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative Biochim. Biophys. Acta Mol. Cell Res. 2013;1833(8):1960-1968 Chamorro, M.E. Wenker, S.D. Vota, D.M. Vittori, D.C. Nesse, A.B. Carbamylated erythropoietin Cell cycle Cell proliferation Erythropoietin FOXO3a P27kip1 carbamylated derivative of erythropoietin cyclin dependent kinase inhibitor 1B erythropoietin transcription factor FKHRL1 unclassified drug apoptosis article cell cycle G1 phase cell cycle progression cell cycle S phase cell differentiation cell proliferation controlled study human human cell neuroblastoma cell priority journal protein expression protein phosphorylation signal transduction Apoptosis Cell Differentiation Cell Growth Processes Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p27 Erythroid Cells Erythropoiesis Erythropoietin Forkhead Transcription Factors G1 Phase Humans Neurons Phosphorylation Receptors, Erythropoietin S Phase Signal Transduction It is now recognized that in addition to its activity upon erythroid progenitor cells, erythropoietin (Epo) is capable of stimulating survival of different non-erythroid cells. Since stimulation of erythropoiesis is unwanted for neuroprotection, Epo-like compounds with a more selective action are under investigation. Although the carbamylated derivative of erythropoietin (cEpo) has demonstrated non-hematopoietic tissue protection without erythropoietic effect, little is known about differential mechanisms between Epo and cEpo. Therefore, we investigated signaling pathways which play a key role in Epo-induced proliferation. Here we show that cEpo blocked FOXO3a phosphorylation, allowing expression of downstream target p27kip1 in UT-7 and TF-1 cells capable of erythroid differentiation. This is consistent with the involvement of cEpo in slowing down G1-to-S-phase progression compared with the effect of Epo upon cell cycle. In contrast, similar antiapoptotic actions of cEpo and Epo were observed in neuronal SH-SY5Y cells. Inhibition and competition assays suggest that Epo may act through both, the homodimeric (EpoR/EpoR) and the heterodimeric (EpoR/βcR) receptors in neuronal SH-SY5Y cells and probably in the TF-1 cell type as well. Results also indicate that cEpo needs both the EpoR and βcR subunits to prevent apoptosis of neuronal cells. Based on evidence suggesting that cell proliferation pathways were involved in the differential effect of Epo and cEpo, we went forward to studying downstream signals. Here we provide the first evidence that unlike Epo, cEpo failed to induce FOXO3a inactivation and subsequent p27kip1 downregulation, which is clearly shown in the incapacity of cEpo to induce erythroid cell growth. © 2013 Elsevier B.V. Fil:Chamorro, M.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Wenker, S.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Vota, D.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Vittori, D.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Nesse, A.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2013 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_01674889_v1833_n8_p1960_Chamorro
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
language	Inglés
orig_language_str_mv	eng
topic	Carbamylated erythropoietin Cell cycle Cell proliferation Erythropoietin FOXO3a P27kip1 carbamylated derivative of erythropoietin cyclin dependent kinase inhibitor 1B erythropoietin transcription factor FKHRL1 unclassified drug apoptosis article cell cycle G1 phase cell cycle progression cell cycle S phase cell differentiation cell proliferation controlled study human human cell neuroblastoma cell priority journal protein expression protein phosphorylation signal transduction Apoptosis Cell Differentiation Cell Growth Processes Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p27 Erythroid Cells Erythropoiesis Erythropoietin Forkhead Transcription Factors G1 Phase Humans Neurons Phosphorylation Receptors, Erythropoietin S Phase Signal Transduction
spellingShingle	Carbamylated erythropoietin Cell cycle Cell proliferation Erythropoietin FOXO3a P27kip1 carbamylated derivative of erythropoietin cyclin dependent kinase inhibitor 1B erythropoietin transcription factor FKHRL1 unclassified drug apoptosis article cell cycle G1 phase cell cycle progression cell cycle S phase cell differentiation cell proliferation controlled study human human cell neuroblastoma cell priority journal protein expression protein phosphorylation signal transduction Apoptosis Cell Differentiation Cell Growth Processes Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p27 Erythroid Cells Erythropoiesis Erythropoietin Forkhead Transcription Factors G1 Phase Humans Neurons Phosphorylation Receptors, Erythropoietin S Phase Signal Transduction Chamorro, M.E. Wenker, S.D. Vota, D.M. Vittori, D.C. Nesse, A.B. Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative
topic_facet	Carbamylated erythropoietin Cell cycle Cell proliferation Erythropoietin FOXO3a P27kip1 carbamylated derivative of erythropoietin cyclin dependent kinase inhibitor 1B erythropoietin transcription factor FKHRL1 unclassified drug apoptosis article cell cycle G1 phase cell cycle progression cell cycle S phase cell differentiation cell proliferation controlled study human human cell neuroblastoma cell priority journal protein expression protein phosphorylation signal transduction Apoptosis Cell Differentiation Cell Growth Processes Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p27 Erythroid Cells Erythropoiesis Erythropoietin Forkhead Transcription Factors G1 Phase Humans Neurons Phosphorylation Receptors, Erythropoietin S Phase Signal Transduction
description	It is now recognized that in addition to its activity upon erythroid progenitor cells, erythropoietin (Epo) is capable of stimulating survival of different non-erythroid cells. Since stimulation of erythropoiesis is unwanted for neuroprotection, Epo-like compounds with a more selective action are under investigation. Although the carbamylated derivative of erythropoietin (cEpo) has demonstrated non-hematopoietic tissue protection without erythropoietic effect, little is known about differential mechanisms between Epo and cEpo. Therefore, we investigated signaling pathways which play a key role in Epo-induced proliferation. Here we show that cEpo blocked FOXO3a phosphorylation, allowing expression of downstream target p27kip1 in UT-7 and TF-1 cells capable of erythroid differentiation. This is consistent with the involvement of cEpo in slowing down G1-to-S-phase progression compared with the effect of Epo upon cell cycle. In contrast, similar antiapoptotic actions of cEpo and Epo were observed in neuronal SH-SY5Y cells. Inhibition and competition assays suggest that Epo may act through both, the homodimeric (EpoR/EpoR) and the heterodimeric (EpoR/βcR) receptors in neuronal SH-SY5Y cells and probably in the TF-1 cell type as well. Results also indicate that cEpo needs both the EpoR and βcR subunits to prevent apoptosis of neuronal cells. Based on evidence suggesting that cell proliferation pathways were involved in the differential effect of Epo and cEpo, we went forward to studying downstream signals. Here we provide the first evidence that unlike Epo, cEpo failed to induce FOXO3a inactivation and subsequent p27kip1 downregulation, which is clearly shown in the incapacity of cEpo to induce erythroid cell growth. © 2013 Elsevier B.V.
format	Artículo Artículo publishedVersion
author	Chamorro, M.E. Wenker, S.D. Vota, D.M. Vittori, D.C. Nesse, A.B.
author_facet	Chamorro, M.E. Wenker, S.D. Vota, D.M. Vittori, D.C. Nesse, A.B.
author_sort	Chamorro, M.E.
title	Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative
title_short	Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative
title_full	Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative
title_fullStr	Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative
title_full_unstemmed	Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative
title_sort	signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative
publishDate	2013
url	http://hdl.handle.net/20.500.12110/paper_01674889_v1833_n8_p1960_Chamorro
work_keys_str_mv	AT chamorrome signalingpathwaysofcellproliferationareinvolvedinthedifferentialeffectoferythropoietinanditscarbamylatedderivative AT wenkersd signalingpathwaysofcellproliferationareinvolvedinthedifferentialeffectoferythropoietinanditscarbamylatedderivative AT votadm signalingpathwaysofcellproliferationareinvolvedinthedifferentialeffectoferythropoietinanditscarbamylatedderivative AT vittoridc signalingpathwaysofcellproliferationareinvolvedinthedifferentialeffectoferythropoietinanditscarbamylatedderivative AT nesseab signalingpathwaysofcellproliferationareinvolvedinthedifferentialeffectoferythropoietinanditscarbamylatedderivative
_version_	1769810179903193088

Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative

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