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. |
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| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
proopiomelanocortin
Receptors Steroid enzyme induction Pro-Opiomelanocortin Transcription Genetic transcription factor Elk 1 Corticotropin-Releasing Hormone cell receptor hypophysis Receptors Cytoplasmic and Nuclear animal cell stress Mice Cyclic AMP animal genetics Phosphorylation Elk1 protein mouse transcription factor stimulus response Cells Cultured mitogen activated protein kinase drug effect article DNA responsive element Calcium Channel Blockers DNA-Binding Proteins nifedipine oncoprotein priority journal Pituitary Gland Promoter Regions (Genetics) point mutation transcription regulation signal transduction hypothalamus hypophysis adrenal system MAP Kinase Signaling System gene overexpression Response Elements Nurr1 nuclear receptor promoter region Proto-Oncogene Proteins corticotropin releasing factor Animalia Animals protein kinase (calcium calmodulin) mouse ets-Domain Protein Elk-1 cyclic AMP dependent protein kinase cell culture calcium nonhuman genetic transcription cell type steroid receptor enzyme activation corticotropin release Cyclic AMP-Dependent Protein Kinases DNA binding protein nuclear receptor Nur77 protein phosphorylation calcium channel blocking agent Mutation cytology corticosteroid receptor metabolism Transcription Factors |
| Zdroj: | Mol. Endocrinol. 2002;16(7):1638-1651 Biblioteca Digital (UBA-FCEN) Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales instacron:UBA-FCEN |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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