title: Control of gp130 expression by the mitogen-activated protein kinase ERK2.
abstract: Interleukin (IL)-6-type cytokines such as IL-6, oncostatin M (OSM) and leukaemia inhibitory factor (LIF) signal through receptor complexes that are critically dependent on gp130. The latter is the common signal-transducing molecule that couples these cytokines to their downstream effectors, Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). IL-6-type cytokine signalling additionally involves the recruitment and activation of extracellular signal-regulated kinase (ERK) 1 and ERK2. Both STATs and ERKs regulate responses mediated by members of the IL-6 family. Here, we show that ERK2, but not ERK1, also controls the expression and function of gp130 per se, as silencing ERK2 in human osteosarcoma U2OS cells inhibits the expression of gp130. This does not simply reflect quantitative differences between ERK1 and ERK2, and the effects are not restricted to osteosarcoma cells, as they can be extended to several other cancer cell types analysed to date (such as breast, prostate, lung and cervical cancer cells). Importantly, ERK2 binds to the GP130 promoter, where it perhaps interacts with the transcriptional machinery. Indeed, its role in the transcriptional regulation of the GP130 gene was corroborated using luciferase reporter assays and messenger RNA stability experiments. Considering the pivotal role that gp130 has in cancer and inflammation these data thus identify novel non-overlapping functions for ERK1 and ERK2 that are biologically relevant.
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: N A
authors.initials: NA
authors.lastname: Bonito
authors.affiliation: Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Drechsler
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Stoecker
authors.affiliation: 1] Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK [2] Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: C R
authors.initials: CR
authors.lastname: Carmo
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany.
authors.forename: H M
authors.initials: HM
authors.lastname: Hermanns
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Costa-Pereira
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3