Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways

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Nur factors are critical for proopiomelanocortin (POMC) induction by CRH in corticotrophs, but the pathways linking CRH to Nur are unknown. In this study we show that in AtT-20 corticotrophs CRH and cAMP induce Nur77 and Nurr1 expression and transcription at the NurRE site by protein kinase A (PKA)...

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Autores principales:	Kovalovsky, D., Refojo, D., Liberman, A.C., Hochbaum, D., Pereda, M.P., Coso, O.A., Stalla, G.K., Holsboer, F., Arzt, E.
Formato:	Artículo publishedVersion
Lenguaje:	Inglés
Publicado:	2002
Materias:	corticosteroid receptor cyclic AMP dependent protein kinase mitogen activated protein kinase proopiomelanocortin protein kinase (calcium,calmodulin) calcium calcium channel blocking agent cell receptor corticotropin releasing factor cyclic AMP DNA binding protein Elk1 protein, mouse nifedipine nuclear receptor Nur77 Nurr1 nuclear receptor oncoprotein steroid receptor transcription factor transcription factor Elk 1 animal cell article cell type corticotropin release enzyme activation enzyme induction gene overexpression hypothalamus hypophysis adrenal system nonhuman point mutation priority journal protein phosphorylation stimulus response stress transcription regulation animal cell culture cytology DNA responsive element drug effect genetic transcription genetics hypophysis metabolism mouse mutation phosphorylation promoter region signal transduction Animalia Animals Calcium Calcium Channel Blockers Cells, Cultured Corticotropin-Releasing Hormone Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA-Binding Proteins ets-Domain Protein Elk-1 MAP Kinase Signaling System Mice Mutation Nifedipine Phosphorylation Pituitary Gland Pro-Opiomelanocortin Promoter Regions (Genetics) Proto-Oncogene Proteins Receptors, Cytoplasmic and Nuclear Receptors, Steroid Response Elements Signal Transduction Transcription Factors Transcription, Genetic
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_08888809_v16_n7_p1638_Kovalovsky
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paperaa:paper_08888809_v16_n7_p1638_Kovalovsky
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spelling	paperaa:paper_08888809_v16_n7_p1638_Kovalovsky2023-06-12T16:48:21Z Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways Mol. Endocrinol. 2002;16(7):1638-1651 Kovalovsky, D. Refojo, D. Liberman, A.C. Hochbaum, D. Pereda, M.P. Coso, O.A. Stalla, G.K. Holsboer, F. Arzt, E. corticosteroid receptor cyclic AMP dependent protein kinase mitogen activated protein kinase proopiomelanocortin protein kinase (calcium,calmodulin) calcium calcium channel blocking agent cell receptor corticotropin releasing factor cyclic AMP DNA binding protein Elk1 protein, mouse nifedipine nuclear receptor Nur77 Nurr1 nuclear receptor oncoprotein steroid receptor transcription factor transcription factor Elk 1 animal cell article cell type corticotropin release enzyme activation enzyme induction gene overexpression hypothalamus hypophysis adrenal system nonhuman point mutation priority journal protein phosphorylation stimulus response stress transcription regulation animal cell culture cytology DNA responsive element drug effect genetic transcription genetics hypophysis metabolism mouse mutation phosphorylation promoter region signal transduction Animalia Animals Calcium Calcium Channel Blockers Cells, Cultured Corticotropin-Releasing Hormone Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA-Binding Proteins ets-Domain Protein Elk-1 MAP Kinase Signaling System Mice Mutation Nifedipine Phosphorylation Pituitary Gland Pro-Opiomelanocortin Promoter Regions (Genetics) Proto-Oncogene Proteins Receptors, Cytoplasmic and Nuclear Receptors, Steroid Response Elements Signal Transduction Transcription Factors Transcription, Genetic Nur factors are critical for proopiomelanocortin (POMC) induction by CRH in corticotrophs, but the pathways linking CRH to Nur are unknown. In this study we show that in AtT-20 corticotrophs CRH and cAMP induce Nur77 and Nurr1 expression and transcription at the NurRE site by protein kinase A (PKA) and calcium-dependent and -independent mechanisms. Calcium pathways depend on calmodulin kinase II (CAMKII) activity, and calcium-independent pathways are accounted for in part by MAPK activation (Rap1/B-Raf/MAPK-ERK kinase/ERK1/2), demonstrated by the use of molecular and pharmacological tools. ATT-20 corticotrophs express B-Raf, as do other cells in which cAMP stimulates MAPK. CRH/cAMP stimulated ERK2 activity and increased transcriptional activity of a Gal4-Elk1 protein, which was blocked by overexpression of dominant negative mutants and kinase inhibitors and stimulated by expression of B-Raf. The MAPK kinase inhibitors did not affect Nur77 and Nurr1 mRNA induction but blocked CRH or cAMP-stimulated Nur transcriptional activity. Moreover, MAPK stimulated phosphorylation and transactivation of Nur77. The functional impact of these pathways was confirmed at the POMC promoter. In conclusion, in AtT-20 corticotrophs the CRH/cAMP signaling that leads to Nur77/Nurr1 mRNA induction and transcriptional activation, and thus POMC expression, is dependent on protein kinase A and involves calcium/calmodulin kinase II (Nur induction/activation) and MAPK calcium-dependent and -independent (Nur phosphorylation-activation) pathways. 2002 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_08888809_v16_n7_p1638_Kovalovsky
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	corticosteroid receptor cyclic AMP dependent protein kinase mitogen activated protein kinase proopiomelanocortin protein kinase (calcium,calmodulin) calcium calcium channel blocking agent cell receptor corticotropin releasing factor cyclic AMP DNA binding protein Elk1 protein, mouse nifedipine nuclear receptor Nur77 Nurr1 nuclear receptor oncoprotein steroid receptor transcription factor transcription factor Elk 1 animal cell article cell type corticotropin release enzyme activation enzyme induction gene overexpression hypothalamus hypophysis adrenal system nonhuman point mutation priority journal protein phosphorylation stimulus response stress transcription regulation animal cell culture cytology DNA responsive element drug effect genetic transcription genetics hypophysis metabolism mouse mutation phosphorylation promoter region signal transduction Animalia Animals Calcium Calcium Channel Blockers Cells, Cultured Corticotropin-Releasing Hormone Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA-Binding Proteins ets-Domain Protein Elk-1 MAP Kinase Signaling System Mice Mutation Nifedipine Phosphorylation Pituitary Gland Pro-Opiomelanocortin Promoter Regions (Genetics) Proto-Oncogene Proteins Receptors, Cytoplasmic and Nuclear Receptors, Steroid Response Elements Signal Transduction Transcription Factors Transcription, Genetic
spellingShingle	corticosteroid receptor cyclic AMP dependent protein kinase mitogen activated protein kinase proopiomelanocortin protein kinase (calcium,calmodulin) calcium calcium channel blocking agent cell receptor corticotropin releasing factor cyclic AMP DNA binding protein Elk1 protein, mouse nifedipine nuclear receptor Nur77 Nurr1 nuclear receptor oncoprotein steroid receptor transcription factor transcription factor Elk 1 animal cell article cell type corticotropin release enzyme activation enzyme induction gene overexpression hypothalamus hypophysis adrenal system nonhuman point mutation priority journal protein phosphorylation stimulus response stress transcription regulation animal cell culture cytology DNA responsive element drug effect genetic transcription genetics hypophysis metabolism mouse mutation phosphorylation promoter region signal transduction Animalia Animals Calcium Calcium Channel Blockers Cells, Cultured Corticotropin-Releasing Hormone Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA-Binding Proteins ets-Domain Protein Elk-1 MAP Kinase Signaling System Mice Mutation Nifedipine Phosphorylation Pituitary Gland Pro-Opiomelanocortin Promoter Regions (Genetics) Proto-Oncogene Proteins Receptors, Cytoplasmic and Nuclear Receptors, Steroid Response Elements Signal Transduction Transcription Factors Transcription, Genetic Kovalovsky, D. Refojo, D. Liberman, A.C. Hochbaum, D. Pereda, M.P. Coso, O.A. Stalla, G.K. Holsboer, F. Arzt, E. Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways
topic_facet	corticosteroid receptor cyclic AMP dependent protein kinase mitogen activated protein kinase proopiomelanocortin protein kinase (calcium,calmodulin) calcium calcium channel blocking agent cell receptor corticotropin releasing factor cyclic AMP DNA binding protein Elk1 protein, mouse nifedipine nuclear receptor Nur77 Nurr1 nuclear receptor oncoprotein steroid receptor transcription factor transcription factor Elk 1 animal cell article cell type corticotropin release enzyme activation enzyme induction gene overexpression hypothalamus hypophysis adrenal system nonhuman point mutation priority journal protein phosphorylation stimulus response stress transcription regulation animal cell culture cytology DNA responsive element drug effect genetic transcription genetics hypophysis metabolism mouse mutation phosphorylation promoter region signal transduction Animalia Animals Calcium Calcium Channel Blockers Cells, Cultured Corticotropin-Releasing Hormone Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA-Binding Proteins ets-Domain Protein Elk-1 MAP Kinase Signaling System Mice Mutation Nifedipine Phosphorylation Pituitary Gland Pro-Opiomelanocortin Promoter Regions (Genetics) Proto-Oncogene Proteins Receptors, Cytoplasmic and Nuclear Receptors, Steroid Response Elements Signal Transduction Transcription Factors Transcription, Genetic
description	Nur factors are critical for proopiomelanocortin (POMC) induction by CRH in corticotrophs, but the pathways linking CRH to Nur are unknown. In this study we show that in AtT-20 corticotrophs CRH and cAMP induce Nur77 and Nurr1 expression and transcription at the NurRE site by protein kinase A (PKA) and calcium-dependent and -independent mechanisms. Calcium pathways depend on calmodulin kinase II (CAMKII) activity, and calcium-independent pathways are accounted for in part by MAPK activation (Rap1/B-Raf/MAPK-ERK kinase/ERK1/2), demonstrated by the use of molecular and pharmacological tools. ATT-20 corticotrophs express B-Raf, as do other cells in which cAMP stimulates MAPK. CRH/cAMP stimulated ERK2 activity and increased transcriptional activity of a Gal4-Elk1 protein, which was blocked by overexpression of dominant negative mutants and kinase inhibitors and stimulated by expression of B-Raf. The MAPK kinase inhibitors did not affect Nur77 and Nurr1 mRNA induction but blocked CRH or cAMP-stimulated Nur transcriptional activity. Moreover, MAPK stimulated phosphorylation and transactivation of Nur77. The functional impact of these pathways was confirmed at the POMC promoter. In conclusion, in AtT-20 corticotrophs the CRH/cAMP signaling that leads to Nur77/Nurr1 mRNA induction and transcriptional activation, and thus POMC expression, is dependent on protein kinase A and involves calcium/calmodulin kinase II (Nur induction/activation) and MAPK calcium-dependent and -independent (Nur phosphorylation-activation) pathways.
format	Artículo Artículo publishedVersion
author	Kovalovsky, D. Refojo, D. Liberman, A.C. Hochbaum, D. Pereda, M.P. Coso, O.A. Stalla, G.K. Holsboer, F. Arzt, E.
author_facet	Kovalovsky, D. Refojo, D. Liberman, A.C. Hochbaum, D. Pereda, M.P. Coso, O.A. Stalla, G.K. Holsboer, F. Arzt, E.
author_sort	Kovalovsky, D.
title	Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways
title_short	Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways
title_full	Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways
title_fullStr	Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways
title_full_unstemmed	Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways
title_sort	activation and induction of nur77/nurr1 in corticotrophs by crh/camp: involvement of calcium, protein kinase a, and mapk pathways
publishDate	2002
url	http://hdl.handle.net/20.500.12110/paper_08888809_v16_n7_p1638_Kovalovsky
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Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways

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