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1.
Nat Immunol ; 5(4): 401-9, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15021879

ABSTRACT

Signal transducer and activator of transcription 3 (STAT3) is the main mediator of interleukin 6 (IL-6)-type cytokine signaling. It exists in two isoforms: the full-length STAT3 alpha and the truncated STAT3 beta, generally thought to act as a dominant negative factor. To assess their relative functions, we ablated the expression of either isoform by gene targeting. We show here that in vivo STAT3 beta is not a dominant negative factor. Its expression can rescue the embryonic lethality of a STAT3-null mutation and it can by itself induce the expression of specific STAT3 target genes. Nevertheless, STAT3 alpha has nonredundant roles such as modulation of cellular responses to IL-6 and mediation of IL-10 function in macrophages.


Subject(s)
DNA-Binding Proteins/metabolism , Fertility/genetics , Trans-Activators/metabolism , Animals , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Genes, Lethal , Immunoblotting , Inflammation/metabolism , Interleukin-6/metabolism , Kidney/pathology , Liver/immunology , Liver/metabolism , Liver/pathology , Lung/pathology , Mice , Mutation , Protein Isoforms/genetics , Protein Isoforms/metabolism , STAT3 Transcription Factor , Trans-Activators/deficiency , Trans-Activators/genetics
2.
J Biol Chem ; 279(14): 13746-54, 2004 Apr 02.
Article in English | MEDLINE | ID: mdl-14742442

ABSTRACT

SOCS-3 (suppressor of cytokine signaling 3) is an intracellular protein that is selectively and rapidly induced by appropriate agonists and that modulates responses of immune cells to cytokines by interfering with the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway. On the basis of the observations that interferon gamma (IFNgamma) up-regulates SOCS-3 gene and protein expression in primary mouse macrophages, J774 macrophage cell line and embryonal fibroblasts, we investigated which sequences of the 5' SOCS-3 gene are responsive to IFNgamma. By promoter deletion analysis we identified a functional IFNgamma-responsive element, located at nucleotides -72/-64 upstream from the transcription initiation, whose presence and integrity is necessary to ensure responsiveness to IFNgamma. This element contains a STAT consensus binding sequence (SOCS-3/STAT-binding element (SBE)) whose specific mutation totally abolished the responsiveness to IFNgamma. In contrast, discrete deletion of other 5' regions of the SOCS-3 promoter did not substantially modify the inducibility by IFNgamma. Electromobility shift assay analyses revealed that IFNgamma promotes specific DNA binding activities to an oligonucleotide probe containing the SOCS-3/SBE sequence. Even though IFNgamma triggered tyrosine phosphorylation of both STAT1 and STAT3 in macrophages and J774 cells, only STAT1 was appropriately activated and thus found to specifically bind to the SOCS-3/SBE oligonucleotide probe. Accordingly, IFNgamma-induced SOCS-3 protein expression was not impaired in STAT3-deficient embryonal fibroblasts. Taken together, these results demonstrate that the induction of SOCS-3 by IFNgamma depends upon the presence of a STAT-binding element in the SOCS-3 promoter that is specifically activated by STAT1.


Subject(s)
Antineoplastic Agents/pharmacology , Interferon-gamma/pharmacology , Macrophages, Peritoneal/physiology , Repressor Proteins/genetics , Transcription Factors/genetics , Animals , Cells, Cultured , DNA-Binding Proteins/metabolism , Gene Expression/drug effects , Gene Expression/immunology , Macrophages, Peritoneal/cytology , Mice , Mice, Inbred C57BL , Mutagenesis , Promoter Regions, Genetic/genetics , STAT1 Transcription Factor , STAT3 Transcription Factor , Signal Transduction/drug effects , Signal Transduction/immunology , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins , Trans-Activators/metabolism
3.
Proc Natl Acad Sci U S A ; 100(16): 9342-7, 2003 Aug 05.
Article in English | MEDLINE | ID: mdl-12867595

ABSTRACT

GRIM-19 (gene associated with retinoid-IFN-induced mortality 19), isolated as a cell death activator in a genetic screen used to define mechanisms involved in IFN-beta- and retinoic acid-induced cell death, codes for a approximately 16-kDa protein that induces apoptosis in a number of cell lines. Antisense ablation of GRIM-19 caused resistance to cell death induced by IFN plus retinoic acid and conferred a growth advantage to cells. To understand the molecular bases for its cell death regulatory activity, we used a yeast two-hybrid screen and identified that the transcription factor STAT3 (signal transducer and activator of transcription 3) binds to GRIM-19. GRIM-19 inhibits transcription driven by activation of STAT3, but not STAT1. It neither inhibits the ligand-induced activation of STAT3 nor blocks its ability to bind to DNA. Mutational analysis indicates that the transactivation domain of STAT3, especially residue S727, is required for GRIM-19 binding. Because GRIM-19 does not bind significantly to other STATs, our studies identify a specific inhibitor of STAT3. Because constitutively active STAT3 up-regulates antiapoptotic genes to promote tumor survival, its inhibition by GRIM-19 also demonstrates an antioncogenic effect exerted by biological therapeutics.


Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , NADH, NADPH Oxidoreductases/physiology , Trans-Activators/antagonists & inhibitors , Animals , Apoptosis , Apoptosis Regulatory Proteins , Cell Death , DNA/metabolism , DNA Mutational Analysis , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/physiology , Humans , Interferon-beta/pharmacology , Ligands , Mice , Oligonucleotide Array Sequence Analysis , Oligonucleotides, Antisense/pharmacology , Plasmids/metabolism , Protein Binding , Protein Structure, Tertiary , STAT1 Transcription Factor , STAT3 Transcription Factor , Serine/chemistry , Trans-Activators/metabolism , Trans-Activators/physiology , Transfection , Tretinoin/pharmacology , Two-Hybrid System Techniques , Up-Regulation
4.
Proc Natl Acad Sci U S A ; 99(12): 8043-7, 2002 Jun 11.
Article in English | MEDLINE | ID: mdl-12060750

ABSTRACT

Signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) is central to the responses to the majority of cytokines and some growth factors, including the interferons (IFNs) and the IL-6 family of cytokines. The biological responses to stimulation through the widely distributed IL-6 and IFN-gamma receptors are, however, completely different. Remarkably, it is shown here that, in mouse embryo fibroblasts lacking STAT3, IL-6 mediates an IFN-gamma-like response including prolonged activation of STAT1, the induction of multiple IFN-gamma-inducible genes, the expression of class II MHC antigens, and an antiviral state. Normal cells exposed to IL-6 thus require a STAT3-dependent function(s) to down-regulate STAT1 activity and prevent an IFN-gamma-like response. The data encourage the view that the very disparate IFN-gamma and IL-6 JAK/receptor complexes mediate a common set of generic or "core" signals which are subject to STAT3-dependent modulation to provide IL-6 specificity. The switching of one cytokine response to one closely mimicking another as a result of the loss of a single signaling component has profound implications, for example, for the interpretation of the phenotypes of knockout mice and for the clinical use of inhibitors of signaling.


Subject(s)
DNA-Binding Proteins/genetics , Interferon-gamma/immunology , Interleukin-6/physiology , Trans-Activators/genetics , Animals , Cell Line , DNA-Binding Proteins/metabolism , Fibroblasts , Genes, MHC Class II/drug effects , Histocompatibility Antigens Class II/genetics , Interleukin-6/pharmacology , Major Histocompatibility Complex/drug effects , Mice , Recombinant Proteins/metabolism , STAT1 Transcription Factor , STAT3 Transcription Factor , Signal Transduction , Trans-Activators/metabolism
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