title: ERK1/2 can feedback-regulate cellular MEK1/2 levels.
abstract: Signal transduction of the Raf/MEK/ERK pathway is regulated by various feedback mechanisms. Given the greater molar ratio between Raf-MEK than between MEK-ERK in cells, it may be possible that MEK1/2 levels are regulated to modulate Raf/MEK/ERK activity upon pathway stimulation. Nevertheless, it has not been reported whether MEK1/2 expression can be subject to a feedback regulation. Here, we report that the Raf/MEK/ERK pathway can feedback-regulate cellular MEK1 and MEK2 levels. In different cell types, ΔRaf-1:ER- or B-Raf(V600E)-mediated MEK/ERK activation increased MEK1 but decreased MEK2 levels. These regulations were abrogated by ERK1/2 knockdown mediated by RNA interference, suggesting the presence of a feedback mechanism that regulates MEK1/2 levels. Subsequently, analyses using qPCR and luciferase reporters of the DNA promoter and 3' untranslated region revealed that the feedback MEK1 upregulation was in part attributed to increased transcription. However, the feedback MEK2 downregulation was only observed at protein levels, which was blocked by the proteasome inhibitors, MG132 and bortezomib, suggesting that the MEK2 regulation is mediated at a post-translational level. These results suggest that the Raf/MEK/ERK pathway can feedback-regulate cellular levels of MEK1 and MEK2, wherein MEK1 levels are upregulated at transcriptional level whereas MEK2 levels are downregulated at posttranslational level.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Seung-Keun
authors.initials: SK
authors.lastname: Hong
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Pui-Kei
authors.initials: PK
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Mansi
authors.initials: M
authors.lastname: Karkhanis
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: jipark@mcw.edu.
authors.forename: Jong-In
authors.initials: JI
authors.lastname: Park
mesh_terms: D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: ERK1/2; Feedback regulation; MEK1; MEK2; Raf