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Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase A, and MAPK pathways

MPS-Authors

Kovalovsky,  D
Max Planck Institute of Psychiatry, Max Planck Society;

Refojo,  D
Max Planck Institute of Psychiatry, Max Planck Society;

Liberman,  AC
Max Planck Institute of Psychiatry, Max Planck Society;

Hochbaum,  D
Max Planck Institute of Psychiatry, Max Planck Society;

Pereda,  MP
Max Planck Institute of Psychiatry, Max Planck Society;

Coso,  OA
Max Planck Institute of Psychiatry, Max Planck Society;

Stalla,  GK
Max Planck Institute of Psychiatry, Max Planck Society;

Holsboer,  F
Max Planck Institute of Psychiatry, Max Planck Society;

Arzt,  E
Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Kovalovsky, D., Refojo, D., Liberman, A., Hochbaum, D., Pereda, M., Coso, O., et al. (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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-A1AD-B
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) pathway