Abstract
Recently, constitutive activation of JAK kinases (JAKs) and/or signal transducers and activators of transcription (STATs) has been reported in growing numbers of human cancer cells as well as oncogene-transformed cells. JAB/SOCS-1 has been shown to be an intrinsic JAK tyrosine kinase inhibitor and to suppress the cytokine-dependent JAK-STAT pathway. In this report, we investigated the effect of ectopic expression of JAB on v-Src-induced JAK-STAT activation. Forced expression of JAB in v-Src-transformed NIH3T3 cells neither suppressed phosphorylation of STAT3 and JAK1/JAK2 nor blocked STAT3-reporter gene activation. Colony forming assay also showed that JAB did not suppress v-Src-induced transformation of NIH3T3 cells, while dominant negative STAT3 suppressed it. In contrast, JAB could downregulate phosphorylation of STAT1 and STAT3 induced by interferon gamma (IFNgamma) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R), respectively. Furthermore, in vitro kinase assay indicated that JAB suppressed hyperactivation of JAK1/JAK2 and JAK1 induced by IFNgamma and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAK1/JAK2 activity. Nevertheless, both JAK1/JAK2 activated by v-Src and that activated by IL-6 plus sIL-6R could similarly bind JAB. These results clearly demonstrate that JAB distinguishes cytokine-induced JAK-STAT signaling from v-Src-induced one and can not suppress the transformation with v-Src.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells / drug effects
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3T3 Cells / metabolism
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Acute-Phase Reaction / genetics
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Amino Acid Substitution
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Animals
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Carrier Proteins / pharmacology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dimerization
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Enzyme Activation / drug effects
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Genes, Reporter
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Humans
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Interferon-gamma / antagonists & inhibitors*
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Interferon-gamma / pharmacology
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Interleukin-6 / antagonists & inhibitors*
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Interleukin-6 / pharmacology
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 1
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Janus Kinase 2
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Mice
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Oncogene Protein pp60(v-src) / physiology*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects*
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins*
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Receptors, Interleukin-6 / physiology
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Regulatory Sequences, Nucleic Acid
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Repressor Proteins*
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction / drug effects*
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Solubility
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transfection
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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Receptors, Interleukin-6
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Repressor Proteins
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SOCS1 protein, human
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Socs1 protein, mouse
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Stat1 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Interferon-gamma
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Protein-Tyrosine Kinases
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JAK1 protein, human
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JAK2 protein, human
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Jak1 protein, mouse
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Jak2 protein, mouse
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Janus Kinase 1
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Janus Kinase 2
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Oncogene Protein pp60(v-src)