title: Adrenocorticotropin induces mitogen-activated protein kinase phosphatase 1 in Y1 mouse adrenocortical tumor cells.
abstract: ACTH signaling pathway includes the action of both protein kinases, mainly cAMP-dependent protein kinase (protein kinase A, PKA), and serine/threonine and tyrosine phosphatases. MAPK phosphatase-1 (MKP-1) is a dual activity protein phosphatase involved in the dephosphorylation of MAPK. To determine whether MKP-1 is a component of ACTH cascade, here we investigate the expression levels of MKP-1 gene in Y1 mouse adrenocortical tumor cells under ACTH stimulation. ACTH transiently increased MKP-1 mRNA and protein levels. MKP-1 mRNA increase occurred at 30 min, peaked at 1 h (6-fold), and returned to basal levels thereafter. The ACTH-mediated mRNA increase was blunted by actinomycin D and enhanced by cycloheximide. A cell permeable cAMP analog, 8-bromo-cAMP, also transiently induced MKP-1 mRNA (4-fold) and the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamid abolished this effect. In contrast, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamid only partially reduced the effect of ACTH, suggesting the participation of PKA-independent mechanisms in the hormone-induced MKP-1 expression. In addition, we show that the rise in intracellular Ca(2+) and protein kinase C activation had a potent synergic effect on ACTH- and 8-bromo-cAMP-mediated MKP-1 induction. In summary, our findings demonstrate that MKP-1 is another component of ACTH signaling cascade and indicate that this hormone may potentially down-regulate MAPKs.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Buenos Aires, Buenos Aires C1121ABG, Argentina.
authors.forename: Paula
authors.initials: P
authors.lastname: Bey
authors.forename: Alejandra B
authors.initials: AB
authors.lastname: Gorostizaga
authors.forename: Paula M
authors.initials: PM
authors.lastname: Maloberti
authors.forename: Rocío Castilla
authors.initials: RC
authors.lastname: Lozano
authors.forename: Cecilia
authors.initials: C
authors.lastname: Poderoso
authors.forename: Fabiana
authors.initials: F
authors.lastname: Cornejo Maciel
authors.forename: Ernesto J
authors.initials: EJ
authors.lastname: Podestá
authors.forename: Cristina
authors.initials: C
authors.lastname: Paz
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000306:Adrenal Cortex Neoplasms; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D018797:Cell Cycle Proteins; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D007546:Isoquinolines; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000324:Adrenocorticotropic Hormone; D003513:Cycloheximide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide