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Abstract:

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.

Registro:

Documento: Artículo
Título:Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways
Autor:Kovalovsky, D.; Refojo, D.; Liberman, A.C.; Hochbaum, D.; Pereda, M.P.; Coso, O.A.; Stalla, G.K.; Holsboer, F.; Arzt, E.
Filiación:Laboratorio de Fisiología y Biología Molecular, Departamento de Biología, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina
Max Planck Institute of Psychiatry, 80804 Munich, Germany
Laboratorio de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria (1428), Buenos Aires, Argentina
Palabras clave: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
Año:2002
Volumen:16
Número:7
Página de inicio:1638
Página de fin:1651
DOI: http://dx.doi.org/10.1210/mend.16.7.0863
Título revista:Molecular Endocrinology
Título revista abreviado:Mol. Endocrinol.
ISSN:08888809
CODEN:MOENE
CAS:cyclic AMP dependent protein kinase; mitogen activated protein kinase, 142243-02-5; proopiomelanocortin, 66796-54-1; calcium, 7440-70-2, 14092-94-5; corticotropin releasing factor, 9015-71-8, 178359-01-8, 79804-71-0, 86297-72-5, 86784-80-7; cyclic AMP, 60-92-4; nifedipine, 21829-25-4; Calcium, 7440-70-2; Calcium Channel Blockers; Corticotropin-Releasing Hormone, 9015-71-8; Cyclic AMP, 60-92-4; Cyclic AMP-Dependent Protein Kinases, EC 2.7.1.37, 7440-70-2; DNA-Binding Proteins; Elk1 protein, mouse; ets-Domain Protein Elk-1; Nifedipine, 21829-25-4, 9015-71-8; Nurr1 nuclear receptor; orphan nuclear receptor NGFI-B, 121479-42-3; Pro-Opiomelanocortin, 66796-54-1; Proto-Oncogene Proteins; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Transcription Factors
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_08888809_v16_n7_p1638_Kovalovsky.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08888809_v16_n7_p1638_Kovalovsky

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Citas:

---------- APA ----------
Kovalovsky, D., Refojo, D., Liberman, A.C., Hochbaum, D., Pereda, M.P., Coso, O.A., Stalla, G.K.,..., Arzt, E. (2002) . Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways. Molecular Endocrinology, 16(7), 1638-1651.
http://dx.doi.org/10.1210/mend.16.7.0863
---------- CHICAGO ----------
Kovalovsky, D., Refojo, D., Liberman, A.C., Hochbaum, D., Pereda, M.P., Coso, O.A., et al. "Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways" . Molecular Endocrinology 16, no. 7 (2002) : 1638-1651.
http://dx.doi.org/10.1210/mend.16.7.0863
---------- MLA ----------
Kovalovsky, D., Refojo, D., Liberman, A.C., Hochbaum, D., Pereda, M.P., Coso, O.A., et al. "Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways" . Molecular Endocrinology, vol. 16, no. 7, 2002, pp. 1638-1651.
http://dx.doi.org/10.1210/mend.16.7.0863
---------- VANCOUVER ----------
Kovalovsky, D., Refojo, D., Liberman, A.C., Hochbaum, D., Pereda, M.P., Coso, O.A., et al. 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.
http://dx.doi.org/10.1210/mend.16.7.0863