title: Cross talk between p38MAPK and ERK is mediated through MAPK-mediated protein phosphatase 2A catalytic subunit α and MAPK phosphatase-1 expression in human leukemia U937 cells.
abstract: This study explores the signaling transduction cascade of ERK and p38 MAPK on regulating MAPK phosphatase-1 (MKP-1) and protein phosphatase 2A catalytic subunit α (PP2Acα) expression in caffeine-treated human leukemia U937 cells. Caffeine induced an increase in the intracellular Ca(2+) concentration and ROS generation leading to p38 MAPK activation and ERK inactivation, respectively. Caffeine treatment elicited MKP-1 down-regulation and PP2Acα up-regulation. The transfection of constitutively active MEK1 or pretreatment with SB202190 (p38 MAPK inhibitor) abolished the caffeine effect on MKP-1 and PP2Acα expression. Caffeine repressed ERK-mediated c-Fos phosphorylation but evoked p38 MAPK-mediated CREB phosphorylation. Knockdown of c-Fos and CREB by siRNA showed that c-Fos and CREB were responsible for MKP-1 and PP2Acα expression, respectively. Promoter and chromatin immunoprecipitating assay supported the role of c-Fos and CREB in regulating MKP-1 and PP2Acα expression. Moreover, transfection of dominant negative MKP-1 cDNA led to p38 MAPK activation and PP2Acα down-regulation in U937 cells, while PP2A inhibitor attenuated caffeine-induced ERK inactivation and MKP-1 down-regulation. Taken together, our data indicate that a reciprocal relationship between ERK-mediated MKP-1 expression and p38 MAPK-mediated PP2Acα expression crucially regulates ERK and p38 MAPK phosphorylation in U937 cells.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Liu
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Tian-Lu
authors.initials: TL
authors.lastname: Cheng
authors.forename: Shinne-Ren
authors.initials: SR
authors.lastname: Lin
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D002110:Caffeine / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002110:Caffeine; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D054638:Dual Specificity Phosphatase 1