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

En:

Mol. Endocrinol. 2002;16(7):1638-1651

Fecha:

2002

Formato:

application/pdf

Tipo de documento:

info:eu-repo/semantics/article
info:ar-repo/semantics/artículo
info:eu-repo/semantics/publishedVersion

Descriptores:

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

Descripción:

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.

Identificador(es):

http://hdl.handle.net/20.500.12110/paper_08888809_v16_n7_p1638_Kovalovsky

Derechos:

info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/2.5/ar