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

Kovalovsky, D. - Refojo, D. - Liberman, A.C. - Hochbaum, D. - Pereda, M.P. - Coso, O.A. - Stalla, G.K. - Holsboer, F. - Arzt, E.
Tipo de documento: 
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.
Mol. Endocrinol. 2002;16(7):1638-1651

Cita bibliográfica:

Kovalovsky, D. ; Refojo, D. ; Liberman, A.C. ; et al. (2002).  Activation and induction of Nur77/Nurr1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways.  (info:eu-repo/semantics/article).  [consultado:  ] Disponible en el Repositorio Digital Institucional de la Universidad de Buenos Aires:  <http://hdl.handle.net/20.500.12110/paper_08888809_v16_n7_p1638_Kovalovsky>