Activation of Jak-Stat and MAPK2 pathways by oncostatin M leads to growth inhibition of human glioma cells.
Oncostatin M (OSM) is a cytokine of the IL-6 family that modulates the growth of various cell types, at least in vitro. We have recently described that OSM inhibits growth and changes cell morphology of human glioma cell lines. Although leukemia inhibitory factor (LIF) receptor components are also expressed by these cells, the response to LIF was significantly weaker compared to OSM. We have therefore analyzed the signal transduction pathways induced by these cytokines. While OSM induces a number of strong tyrosine phosphorylations, including Janus tyrosine kinases (Jak) and the signal transducer and activator of transcription (Stat) proteins, LIF induces only minor tyrosine phosphorylation of Tyk2 and Stat3. Specific activation of the tyrosine phosphatase SHP-2 as well as the mitogen-activated kinase 2 (MAPK2) was found in glioma cells upon OSM treatment. MAPK2 turns out to be a crucial mediator of the OSM effect in glioma cells since inhibition of MAPK activity by the Mek1 inhibitor PD98059 blocks the OSM-induced inhibition of DNA synthesis by about 70%.
Halfter
H
H
Clinic of Neurology, Westf. Wilhelms-Universität Münster, Germany. halfter@uni-muenster.de
Friedrich
M
M
Postert
C
C
Ringelstein
E B
EB
Stögbauer
F
F
D015153:Blotting, Western; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005910:Glioma; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine / Q000378:metabolism; D053606:Receptors, OSM-LIF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008894:Milk Proteins; C508351:OSM protein, human; D010455:Peptides; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D053683:Oncostatin M; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D019950:Mitogen-Activated Protein Kinase 1