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Curt M Horvath - One of the best experts on this subject based on the ideXlab platform.

  • STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling.
    Journal of Virology, 2003
    Co-Authors: Christina M. Ulane, Jean Patrick Parisien, Jason J. Rodriguez, Curt M Horvath
    Abstract:

    Mumps virus is a common infectious agent of humans, causing parotitis, meningitis, encephalitis, and orchitis. Like other paramyxoviruses in the genus Rubulavirus, mumps virus catalyzes the proteasomal degradation of cellular STAT1 Protein, a means for escaping antiviral responses initiated by alpha/beta and gamma interferons. We demonstrate that mumps virus also eliminates cellular STAT3, a Protein that mediates transcriptional responses to cytokines, growth factors, nonreceptor tyrosine kinases, and a variety of oncogenic stimuli. STAT1 and STAT3 are independently targeted by a single mumps virus Protein, called V, that assembles STAT-directed ubiquitylation complexes from cellular components, including STAT1, STAT2, STAT3, DDB1, and Cullin4A. Consequently, mumps virus V Protein prevents responses to interleukin-6 and v-Src signals and can induce apoptosis in STAT3-dependent multiple myeloma cells and transformed murine fibroblasts. These findings demonstrate a unique cytokine and oncogene evasion property of mumps virus that provides a molecular basis for its observed oncolytic properties.

  • transcriptionally active STAT1 is required for the antiproliferative effects of both interferon alpha and interferon gamma
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Jacqueline Bromberg, Curt M Horvath, Zilong Wen, Robert D Schreiber, James E. Darnell
    Abstract:

    Abstract Type I (alpha, beta) and type II (gamma) interferons (IFNs) can restrict the growth of many cell types. INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus kinase-signal transducers and activators of transcription pathway, in which both IFN-alpha and IFN-gamma activate the transcription factor STAT1. A cell line lacking STAT1 (U3A) was not growth-arrested by IFN-alpha or IFN-gamma, and experiments were carried out with U3A cells permanently expressing normal or various mutant forms of STAT1 Protein. Only cells in which complete STAT1 activity was available (STAT1alpha) were growth-inhibited by IFN-gamma. A mutant that supports 20-30% normal transcription did not cause growth restraint. In contrast, IFN-alpha growth restraint was imposed by cells producing STAT1beta, which lacks transcriptional activation potential. This parallels earlier results showing the truncated STAT1 can function in IFN-alpha gene activation. In addition to experiments on long-term cultured cells, we also found that wild-type primary mouse embryonic fibroblasts were inhibited by IFNs, but fibroblasts from STAT1-deficient mouse embryos were not inhibited by IFNs.

  • The antiviral state induced by alpha interferon and gamma interferon requires transcriptionally active STAT1 Protein.
    Journal of virology, 1996
    Co-Authors: Curt M Horvath, James E. Darnell
    Abstract:

    Both of the latent transcription factors activated by alpha interferon or gamma interferon contain the STAT1 Protein. The role of STAT1 in virus interference mediated by interferons was directly examined by using cultured cells expressing STAT1 Protein and its variants. In the absence of STAT1, no antiviral state is established. Full complementation of the antiviral state requires full-length STAT1 which is phosphorylated on both tyrosine 701 and serine 727. The closely related signal transducer and activator of transcription Protein Stat3 cannot substitute for the antiviral properties of STAT1.

Paul C. Kuo - One of the best experts on this subject based on the ideXlab platform.

  • Osteopontin mediates STAT1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis.
    Surgery, 2008
    Co-Authors: Hongtao Guo, Chengjiang Gao, Philip Y. Wai, Jinping Zhang, Paul C. Kuo
    Abstract:

    Background Osteopontin (OPN) represses inducible nitric oxide synthase (iNOS) expression by increasing ubiquitin (Ub)-proteasome degradation of STAT1, a critical transcription factor for iNOS expression. We investigated the in vivo relevance of our findings in a cecal ligation and puncture model. Methods and Results A total of 129 wild-type (WT; n = 24) and OPN null (n = 24) mice were used. Bone marrow macrophages and whole liver tissue were isolated. iNOS and phosphorylated Stat-1 (P-STAT1) Protein were significantly greater in OPN null than WT. Cecal ligation and puncture increased Ub-P-STAT1; Ub-P-STAT1 was significantly less in OPN null than WT. In chromatin immunoprecipitation assays, P-STAT1 binding to the iNOS promoter was increased in OPN null. Ex vivo studies with bone marrow macrophages were performed with MG132 (10 μM), an inhibitor of 26S proteasome function, and/or exogenous OPN (50 μM). Ub-P-STAT1 was decreased in OPN null bone marrow macrophages treated with LPS; iNOS was increased. Exogenous OPN or MG132 restored Ub-P-STAT1 and iNOS to levels seen in WT. Our results indicate that absence of OPN does the following: (1) increases iNOS and P-STAT1 Protein, (2) decreases ubiquitination and degradation of P-STAT1, and (3) increases iNOS transcription. Conclusions We conclude that OPN downregulates iNOS expression by accelerating ubiquitination and degradation of STAT1.

  • 205. Osteopontin Mediates STAT1 Degradation to Inhibit iNOS Transcription in a Cecal Ligation and Puncture Model of Sepsis
    Journal of Surgical Research, 2008
    Co-Authors: Hongtao Guo, Chengjiang Gao, Philip Y. Wai, Jinping Zhang, Paul C. Kuo
    Abstract:

    Background. Osteopontin (OPN) represses inducible nitric oxide synthase (iNOS) expression by increasing ubiquitin (Ub)-proteasome degradation of STAT1, a critical transcription factor for iNOS expression. We investigated the in vivo relevance of our findings in a cecal ligation and puncture model. Methods and Results. A total of 129 wild-type (WT; n = 24) and OPN null (n = 24) mice were used. Bone marrow macrophages and whole liver tissue were isolated. iNOS and phosphorylated STAT1 (P-STAT1) Protein were significantly greater in OPN null than WT. Cecal ligation and puncture increased Ub-P-STAT1; Ub-P-STAT1 was significantly less in OPN null than WT. In chromatin immunoprecipitation assays, P-STAT1 binding to the iNOS promoter was increased in OPN null. Ex vivo studies with bone marrow macrophages were performed with MG132 (10 mM), an inhibitor of 26S proteasome function, and/or exogenous OPN (50 mM). Ub-P-STAT1 was decreased in OPN null bone marrow macrophages treated with LPS; iNOS was increased. Exogenous OPN or MG132 restored Ub-P-STAT1 and iNOS to levels seen in WT. Our results indicate that absence of OPN does the following: (1) increases iNOS and P-STAT1 Protein, (2) decreases ubiquitination and degradation of P-STAT1, and (3) increases iNOS transcription. Conclusions. We conclude that OPN downregulates iNOS expression by accelerating ubiquitination and degradation of STAT1. (Surgery 2008;144:182-8.)

  • STAT1 acetylation inhibits inducible nitric oxide synthase expression in interferon-γ-treated RAW264.7 murine macrophages
    Surgery, 2007
    Co-Authors: Lucie Guo, Hongtao Guo, Chengjiang Gao, William B. Russell, Paul C. Kuo
    Abstract:

    Background We hypothesized that acetylation of the STAT1 regulates interferon-γ (IFN-γ) mediated macrophage expression of inducible nitric oxide synthase (iNOS). Methods RAW 264.7 iNOS expression was induced with IFN-γ. Deacetylase inhibitors trichostatin A (TSA) or valproic acid (VPA) were added. STAT1 and iNOS mRNA and Protein were measured. Acetylated STAT1 was determined by immunoprecipitation. Chromatin immunoprecipitation assessed in vivo binding of STAT1 to the iNOS promoter. Results IFN-γ significantly increased nitrite, iNOS Protein and iNOS mRNA, and iNOS promoter activation. ( P P P P Conclusions Acetylation of STAT1 Protein correlates with decreased STAT1 binding to the iNOS promoter with resultant inhibition of IFN-γ–mediated iNOS expression. Acetylation of the STAT1 Protein may downregulate iNOS expression in proinflammatory states.

Chengjiang Gao - One of the best experts on this subject based on the ideXlab platform.

  • smurf1 Protein negatively regulates interferon γ signaling through promoting STAT1 Protein ubiquitination and degradation
    Journal of Biological Chemistry, 2012
    Co-Authors: Chao Yuan, Xueying Zhao, Chengjiang Gao
    Abstract:

    Interferons are important cytokines that mediate antiviral, antiproliferative, antitumor, and immunoregulatory activities. However, uncontrolled IFN signaling may lead to autoimmune diseases. Here we identified Smurf1 as a negative regulator for IFN-γ signaling by targeting STAT1 for ubiquitination and proteasomal degradation. Smurf1 interacted with STAT1 through the WW domains of Smurf1 and the PY motif in STAT1 and catalyzed K48-linked polyubiquitination of STAT1. Interestingly, the Smurf1-mediated ubiquitination and degradation did not require STAT1 tyrosine and serine phosphorylation. Subsequently, overexpression of Smurf1 attenuated IFN-γ-mediated STAT1 activation and antiviral immune responses, whereas knockdown of Smurf1 enhanced IFN-γ-mediated STAT1 activation, expression of STAT1 target genes, and antiviral immune responses. Furthermore, IFN-γ stimulation led to enhanced expression of Smurf1. Therefore, our results demonstrate that Smurf1 is a negative feedback regulator for IFN-γ signaling by targeting STAT1 for ubiquitination and proteasomal degradation.

  • Smurf1 Protein negatively regulates interferon-γ signaling through promoting STAT1 Protein ubiquitination and degradation
    The Journal of biological chemistry, 2012
    Co-Authors: Chao Yuan, Xueying Zhao, Chengjiang Gao
    Abstract:

    Abstract Interferons are important cytokines that mediate anti-viral, anti-proliferative, anti-tumor and immuno-regulatory activities. But, uncontrolled IFN signaling may lead to autoimmune diseases. Here we identified Smurf1 as a negative regulator for IFN-gamma signaling by targeting STAT1 for unbiquitination and proteasomal degradation. Smurf1 interacted with STAT1 through the WW domains of Smurf1 and the PY motif in STAT1, and catalyzed K48-linked polyubiquitination of STAT1. Interestingly, the Smurf1-mediated ubiquitination and degradation did not require STAT1 tyrosine and serine phosphorylation. Subsequently, overexpression of Smurf1 attenuated IFN-gamma-mediated STAT1 activation and anti-viral immune responses, while knockdown of Smurf1 enhanced IFN-gamma-mediated STAT1 activation, expression of STAT1 target genes and anti-viral immune responses. Furthermore, IFN-gamma stimulation led to enhanced expression of Smurf1. Therefore, our results demonstrate that Smurf1 is a negative feedback regulator for IFN-gamma signaling by targeting STAT1 for ubiquitination and proteasomal degradation.

  • Osteopontin mediates STAT1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis.
    Surgery, 2008
    Co-Authors: Hongtao Guo, Chengjiang Gao, Philip Y. Wai, Jinping Zhang, Paul C. Kuo
    Abstract:

    Background Osteopontin (OPN) represses inducible nitric oxide synthase (iNOS) expression by increasing ubiquitin (Ub)-proteasome degradation of STAT1, a critical transcription factor for iNOS expression. We investigated the in vivo relevance of our findings in a cecal ligation and puncture model. Methods and Results A total of 129 wild-type (WT; n = 24) and OPN null (n = 24) mice were used. Bone marrow macrophages and whole liver tissue were isolated. iNOS and phosphorylated Stat-1 (P-STAT1) Protein were significantly greater in OPN null than WT. Cecal ligation and puncture increased Ub-P-STAT1; Ub-P-STAT1 was significantly less in OPN null than WT. In chromatin immunoprecipitation assays, P-STAT1 binding to the iNOS promoter was increased in OPN null. Ex vivo studies with bone marrow macrophages were performed with MG132 (10 μM), an inhibitor of 26S proteasome function, and/or exogenous OPN (50 μM). Ub-P-STAT1 was decreased in OPN null bone marrow macrophages treated with LPS; iNOS was increased. Exogenous OPN or MG132 restored Ub-P-STAT1 and iNOS to levels seen in WT. Our results indicate that absence of OPN does the following: (1) increases iNOS and P-STAT1 Protein, (2) decreases ubiquitination and degradation of P-STAT1, and (3) increases iNOS transcription. Conclusions We conclude that OPN downregulates iNOS expression by accelerating ubiquitination and degradation of STAT1.

  • 205. Osteopontin Mediates STAT1 Degradation to Inhibit iNOS Transcription in a Cecal Ligation and Puncture Model of Sepsis
    Journal of Surgical Research, 2008
    Co-Authors: Hongtao Guo, Chengjiang Gao, Philip Y. Wai, Jinping Zhang, Paul C. Kuo
    Abstract:

    Background. Osteopontin (OPN) represses inducible nitric oxide synthase (iNOS) expression by increasing ubiquitin (Ub)-proteasome degradation of STAT1, a critical transcription factor for iNOS expression. We investigated the in vivo relevance of our findings in a cecal ligation and puncture model. Methods and Results. A total of 129 wild-type (WT; n = 24) and OPN null (n = 24) mice were used. Bone marrow macrophages and whole liver tissue were isolated. iNOS and phosphorylated STAT1 (P-STAT1) Protein were significantly greater in OPN null than WT. Cecal ligation and puncture increased Ub-P-STAT1; Ub-P-STAT1 was significantly less in OPN null than WT. In chromatin immunoprecipitation assays, P-STAT1 binding to the iNOS promoter was increased in OPN null. Ex vivo studies with bone marrow macrophages were performed with MG132 (10 mM), an inhibitor of 26S proteasome function, and/or exogenous OPN (50 mM). Ub-P-STAT1 was decreased in OPN null bone marrow macrophages treated with LPS; iNOS was increased. Exogenous OPN or MG132 restored Ub-P-STAT1 and iNOS to levels seen in WT. Our results indicate that absence of OPN does the following: (1) increases iNOS and P-STAT1 Protein, (2) decreases ubiquitination and degradation of P-STAT1, and (3) increases iNOS transcription. Conclusions. We conclude that OPN downregulates iNOS expression by accelerating ubiquitination and degradation of STAT1. (Surgery 2008;144:182-8.)

  • STAT1 acetylation inhibits inducible nitric oxide synthase expression in interferon-γ-treated RAW264.7 murine macrophages
    Surgery, 2007
    Co-Authors: Lucie Guo, Hongtao Guo, Chengjiang Gao, William B. Russell, Paul C. Kuo
    Abstract:

    Background We hypothesized that acetylation of the STAT1 regulates interferon-γ (IFN-γ) mediated macrophage expression of inducible nitric oxide synthase (iNOS). Methods RAW 264.7 iNOS expression was induced with IFN-γ. Deacetylase inhibitors trichostatin A (TSA) or valproic acid (VPA) were added. STAT1 and iNOS mRNA and Protein were measured. Acetylated STAT1 was determined by immunoprecipitation. Chromatin immunoprecipitation assessed in vivo binding of STAT1 to the iNOS promoter. Results IFN-γ significantly increased nitrite, iNOS Protein and iNOS mRNA, and iNOS promoter activation. ( P P P P Conclusions Acetylation of STAT1 Protein correlates with decreased STAT1 binding to the iNOS promoter with resultant inhibition of IFN-γ–mediated iNOS expression. Acetylation of the STAT1 Protein may downregulate iNOS expression in proinflammatory states.

James E. Darnell - One of the best experts on this subject based on the ideXlab platform.

  • transcriptionally active STAT1 is required for the antiproliferative effects of both interferon alpha and interferon gamma
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Jacqueline Bromberg, Curt M Horvath, Zilong Wen, Robert D Schreiber, James E. Darnell
    Abstract:

    Abstract Type I (alpha, beta) and type II (gamma) interferons (IFNs) can restrict the growth of many cell types. INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus kinase-signal transducers and activators of transcription pathway, in which both IFN-alpha and IFN-gamma activate the transcription factor STAT1. A cell line lacking STAT1 (U3A) was not growth-arrested by IFN-alpha or IFN-gamma, and experiments were carried out with U3A cells permanently expressing normal or various mutant forms of STAT1 Protein. Only cells in which complete STAT1 activity was available (STAT1alpha) were growth-inhibited by IFN-gamma. A mutant that supports 20-30% normal transcription did not cause growth restraint. In contrast, IFN-alpha growth restraint was imposed by cells producing STAT1beta, which lacks transcriptional activation potential. This parallels earlier results showing the truncated STAT1 can function in IFN-alpha gene activation. In addition to experiments on long-term cultured cells, we also found that wild-type primary mouse embryonic fibroblasts were inhibited by IFNs, but fibroblasts from STAT1-deficient mouse embryos were not inhibited by IFNs.

  • The antiviral state induced by alpha interferon and gamma interferon requires transcriptionally active STAT1 Protein.
    Journal of virology, 1996
    Co-Authors: Curt M Horvath, James E. Darnell
    Abstract:

    Both of the latent transcription factors activated by alpha interferon or gamma interferon contain the STAT1 Protein. The role of STAT1 in virus interference mediated by interferons was directly examined by using cultured cells expressing STAT1 Protein and its variants. In the absence of STAT1, no antiviral state is established. Full complementation of the antiviral state requires full-length STAT1 which is phosphorylated on both tyrosine 701 and serine 727. The closely related signal transducer and activator of transcription Protein Stat3 cannot substitute for the antiviral properties of STAT1.

Kenzo Kobayashi - One of the best experts on this subject based on the ideXlab platform.

  • Regulation by cAMP of STAT1 Activation in Hepatic Stellate Cells
    Biochemical and biophysical research communications, 1997
    Co-Authors: Norifumi Kawada, Machiko Uoya, Shuichi Seki, Tetsuo Kuroki, Kenzo Kobayashi
    Abstract:

    Abstract Previously we reported that dibutyryl cAMP and phosphodiesterase inhibitor methylxanthines block rat stellate cell proliferation. To analyze the underlying mechanism, modulation by these agents of platelet-derived growth factor (PDGF)/BB-stimulating signal pathway was studied. Without reducing STAT1 Protein level, these agents were found to attenuate STAT1 activation in stellate cells stimulated with PDGF/BB as revealed by an electrophoretic mobility shift assay. Inhibitory effect started 12 h after exposure of the cells to these agents at concentrations of more than 100 μM. These agents had no effects on DNA binding activity of STAT1 that had already been activated. Treatment with these agents failed to affect the function of PDGF receptors except for partial attenuation of phospholipase C activation under PDGF/BB stimulation. The present results indicate that inhibition of STAT1 activation may be one of factors involved in the cAMP-dependent stellate cell growth arrest.