title: SOCS-1 suppresses TNF-alpha-induced apoptosis through the regulation of Jak activation.
abstract: Suppressor of cytokine signaling-1 (SOCS-1) was identified as one of the negative feedback regulators of Janus kinase (Jak)-signal-transducer-and-activator-of-transcription (STAT) signaling. So far, it has been reported that SOCS-1 inhibits the action of multiple cytokines at least in vitro. We previously showed that SOCS-1 suppresses tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in murine embryonic fibroblast, but the mechanism of suppression was not fully clarified. In this study, we show that Jaks bind to TNF receptor-1 (TNFR-1) and are activated by TNF-alpha. We also show that the activations of Jaks and caspases by TNF-alpha are suppressed by SOCS-1. Furthermore, in Jak-deficient cell lines, DNA fragmentation and caspase-8 activation by TNF-alpha are suppressed, indicating that Jaks participate in TNF-alpha-induced apoptosis signaling. Taken together, these results suggest that SOCS-1 inhibits TNF-alpha-induced apoptosis through regulation of Jaks.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan. a.kimura@imed3.med.osaka-u.ac.jp
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kimura
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053613:Janus Kinase 1; D019169:Jurkat Cells; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology*; D012097:Repressor Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases