title: MAP kinase phosphatase-3 (MKP-3) is transcriptionally and post-translationally up-regulated by hCG and modulates cAMP-induced p21 expression in MA-10 Leydig cells.
abstract: Luteinizing hormone (LH) activates ERK1/2, MAP kinases (MAPKs) necessary for its action on steroidogenesis and cell proliferation, and also induces MAPK phosphatase-1 (MKP-1), which rapidly dephosphorylates nuclear ERK1/2. MKP-3 is a cytoplasmic ERK-phosphatase up-regulated by proliferative stimuli. MKP-3 also dephosphorylates transcription factor FOXO1, promoting its transport to the nucleus. Here we analyzed MKP-3 expression in MA-10 Leydig cells and demonstrated that LH receptor (LHR) activation with human gonadotropin hormone (hCG) and an analog of its second messenger, 8Br-cAMP, up-regulates MKP-3 by transcriptional and post-translational mechanisms. It is known that FOXO1 drives the expression of the cell cycle inhibitor p21. Since the activation of this transcription factor by MKP-3 has been reported, we assessed the effect of shRNA against MKP-3 on p21mRNA levels. 8Br-cAMP increased these levels (2-fold at 2h) and MKP-3 down-regulation reduced this effect. Our work demonstrates that LH/hCG tightly up-regulates MKP-3 which in turn, dephosphorylates ERK1/2 and drives p21 expression. These events could contribute to counteract hormonal action on cell proliferation.
authors.affiliation: Institute for Biomedical Research (INBIOMED), Department of Biochemistry, School of Medicine, University of Buenos Aires, Paraguay 2155, (C1121ABG) Buenos Aires, Argentina.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Mori Sequeiros García
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Gómez
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gorostizaga
authors.forename: Andrea
authors.initials: A
authors.lastname: Acquier
authors.forename: Silvia I
authors.initials: SI
authors.lastname: González-Calvar
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Mendez
authors.forename: Cristina
authors.initials: C
authors.lastname: Paz
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006063:Chorionic Gonadotropin; D000242:Cyclic AMP / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D054642:Dual Specificity Phosphatase 6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007985:Leydig Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D011974:Receptors, LH / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D006063:Chorionic Gonadotropin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011974:Receptors, LH; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D054642:Dual Specificity Phosphatase 6