Adrenocorticotropin Induces Mitogen-Activated Protein Kinase Phosphatase 1 in Y1 Mouse Adrenocortical Tumor Cells

• Published in: Endocrinology (Philadelphia) Vol. 144; no. 4; pp. 1399 - 1406
• Main Authors: Bey, Paula, Gorostizaga, Alejandra B, Maloberti, Paula M, Lozano, Rocío Castilla, Poderoso, Cecilia, Maciel, Fabiana Cornejo, Podestá, Ernesto J, Paz, Cristina
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.04.2003; Oxford University Press
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Actinomycin; Adrenal Cortex Neoplasms; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - pharmacology; Adrenocorticotropin (ACTH); Animals; Biological and medical sciences; Calcium (intracellular); Calcium ions; Calcium Signaling - physiology; Cell Cycle Proteins; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cycloheximide; Cycloheximide - pharmacology; Dephosphorylation; Dose-Response Relationship, Drug; Dual Specificity Phosphatase 1; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Intracellular signalling; Isoquinolines - pharmacology; Kinases; MAP kinase; MAP kinase phosphatase; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; mRNA; Phosphatase; Phosphoprotein Phosphatases; Phosphorylation; Protein folding; Protein kinase A; Protein kinase C; Protein phosphatase; Protein Phosphatase 1; Protein Synthesis Inhibitors - pharmacology; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Protein-tyrosine-phosphatase; Proteins; RNA, Messenger - analysis; Signal transduction; Sulfonamides; Transcriptional Activation - drug effects; Tumor cells; Tumor Cells, Cultured; Tumors; Tyrosine
• DOI: 10.1210/en.2002-220987
• ISSN: 0013-7227

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 Ca2+ 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.