Control of gp130 expression by the mitogen-activated protein kinase ERK2

• Published in: Oncogene Vol. 33; no. 17; pp. 2255 - 2263
• Main Authors: Bonito, N A, Drechsler, J, Stoecker, S, Carmo, C R, Seckl, M J, Hermanns, H M, Costa-Pereira, A P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.04.2014; Nature Publishing Group
• Subjects: 631/208/200; 631/80/86; 692/420/755; Apoptosis; Base Sequence; Binding Sites; Bone cancer; Breast; Cancer; Cell Biology; Cell Line, Tumor; Cell research; Cellular control mechanisms; Cervical cancer; Cervix; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Cytokines; Extracellular signal-regulated kinase; Gene Expression; Gene Knockdown Techniques; Gene regulation; Genetic aspects; Glycoprotein gp130; Glycoproteins; Human Genetics; Humans; Interleukin 6; Interleukin-6 - physiology; Internal Medicine; Kinases; Leukemia; Leukemia inhibitory factor; Lung cancer; MAP kinase; MAP Kinase Signaling System; Medicine; Medicine & Public Health; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3 - metabolism; mRNA stability; Oncology; Oncostatin M; original-article; Osteosarcoma; Osteosarcoma cells; Phosphorylation; Phosphotransferases; Physiological aspects; Promoter Regions, Genetic; Properties; Prostate cancer; Protein Binding; Protein kinase; Protein Processing, Post-Translational; Proteins; RNA, Small Interfering - genetics; Sarcoma; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - metabolism; Transcription factors; Transcriptional Activation; gp130; JAK/STAT signalling; receptor expression; IL-6-type cytokines; ERK
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.159

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.