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Molecular Endocrinology 16 (7): 1638-1651
Copyright © 2002 by The Endocrine Society

Activation and Induction of NUR77/NURR1 in Corticotrophs by CRH/cAMP: Involvement of Calcium, Protein Kinase A, and MAPK Pathways

Damián Kovalovsky1, Damián Refojo1, Ana Clara Liberman, Daniel Hochbaum, Marcelo Paez Pereda, Omar A. Coso1, Günter K. Stalla, Florian Holsboer and Eduardo Arzt1

Laboratorio de Fisiología y Biología Molecular (D.K., D.R., A.C.L., D.H., O.A.C., E.A.), Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina; and Max Planck Institute of Psychiatry (M.P.P., G.K.S., F.H.), 80804 Munich, Germany

Address all correspondence and requests for reprints to: Dr. Eduardo Arzt, Laboratorio de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (1428), Buenos Aires, Argentina. E-mail: earzt{at}bg.fcen.uba.ar.

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.




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