title: cAMP-activated Nr4a1 expression requires ERK activity and is modulated by MAPK phosphatase-1 in MA-10 Leydig cells.
abstract: In Leydig cells, LH and cAMP promote ERK1/2 activation and MAPK phosphatase-1 (MKP-1) induction. MKP-1 up-regulation, which involves post-translational modifications such as ERK1/2-mediated phosphorylation, reduces ERK1/2 phosphorylation as well as Steroidogenic Acute Regulatory (StAR) protein expression and steroidogenesis. As LH- and cAMP-promoted StAR transcription requires the induction of Nur77, product of Nr4a1 gene, we analyzed the roles of ERK1/2 and MKP-1 in 8Br-cAMP-mediated Nr4a1 expression in MA-10 Leydig cells. Pharmacological blockade of ERK1/2 activation partially reduced the 8Br-cAMP-mediated increase in both Nr4a1 messenger levels and promoter activity. MKP-1 knock-down increased 8Br-cAMP-induced promoter activity, while its over-expression produced the opposite effect. It is concluded that Nr4a1 induction is dependent on ERK1/2 and that MKP-1 negatively regulates this induction. Experiments based on the over-expression of MKP-1 mutated forms revealed that MKP-1 half life is determined by post-translational modifications in ERK-consensus sites, a regulation that modulates the effect of MKP-1 on Nr4a1 expression.
authors: Institute for Biomedical Research (INBIOMED), Department of Biochemistry, School of Medicine, University of Buenos Aires, Paraguay 2155, (C1121ABG), Buenos Aires, Argentina.
authors: Mercedes
authors: M
authors: Mori Sequeiros Garcia
authors: Institute for Biomedical Research (INBIOMED), Department of Biochemistry, School of Medicine, University of Buenos Aires, Paraguay 2155, (C1121ABG), Buenos Aires, Argentina.
authors: Alejandra
authors: A
authors: Gorostizaga
authors: Membrane Signaling Networks, Department of Medicine, Karolinska Institutet, CMM, Karolinska University Hospital-Solna, Solnavägen 1, 171 77 Solna, Stockholm, Sweden.
authors: Laura
authors: L
authors: Brion
authors: Institute of Biology and Experimental Medicine, National Council for Scientific and Technical Research, Vuelta de Obligado 2490 (C1428DN), Buenos Aires, Argentina; School of Medicine, University of Buenos Aires, Paraguay 2155 (C1121ABG), Buenos Aires, Argentina.
authors: Silvia I
authors: SI
authors: González-Calvar
authors: Institute for Biomedical Research (INBIOMED), Department of Biochemistry, School of Medicine, University of Buenos Aires, Paraguay 2155, (C1121ABG), Buenos Aires, Argentina. Electronic address: crispaz1506@gmail.com.
authors: Cristina
authors: C
authors: Paz
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004795:Enzyme Stability / Q000187:drug effects; D007985:Leydig Cells / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: ERK1/2; Leydig cells; MAP kinase phosphatase; MKP-1; Nr4a1; Nur77