The Experts below are selected from a list of 69738 Experts worldwide ranked by ideXlab platform
Keiko Ozato - One of the best experts on this subject based on the ideXlab platform.
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synergistic activation of interleukin 12 p35 gene transcription by interferon regulatory factor 1 and interferon Consensus Sequence binding protein
Journal of Biological Chemistry, 2004Co-Authors: Jianguo Liu, Tomohiko Tamura, Xiuqin Guan, Keiko OzatoAbstract:Interferon regulatory factor-1 (IRF-1) and interferon Consensus Sequence-binding protein (ICSBP or IRF-8) are two members of the IRF family of transcription factors that play critical roles in interferon signaling in a wide range of host responses to infection and malignancy. Interleukin-12 (IL-12) is a key factor in the induction of innate resistance and generation of T helper type 1 cells and cytotoxic T lymphocytes. In this work, we find that ICSBP-deficient macrophages are highly defective in the production of IL-12. The defect is also observed at the level of IL-12 p40 and p35 mRNA expression. Transcriptional analyses revealed that ICSBP is a potent activator of the IL-12 p35 gene. It acts through a site localized to -226 to -219, named ICSBP-response element (ICSBP-RE), in the human IL-12 p35 promoter through physical association with IRF-1 both in vitro and in vivo. Co-expression of ICSBP and IRF-1 synergistically stimulates the IL-12 p35 promoter activity. Mutations at the ICSBP-RE results in the loss of protein binding as well as transcriptional activation by ICSBP alone or together with IRF-1. This study provides novel mechanistic information on how signals initiated during innate and adaptive immune responses synergize to yield greater IL-12 production and sustained cellular immunity.
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toll like receptor 9 signaling activates nf κb through ifn regulatory factor 8 ifn Consensus Sequence binding protein in dendritic cells
Journal of Immunology, 2004Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Hee Jeong Kong, Akira Nishiyama, Ken J Ishii, Dennis M Klinman, Keiko OzatoAbstract:Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-κB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN Consensus Sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8−/− mice were unresponsive to CpG and failed to induce TNF-α and IL-6, targets of NF-κB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8−/− DCs in response to LPS that signals through TLR4. IRF-8−/− DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-κB in −/− cells. This was due to the selective inability of −/− DCs to activate I-κB kinase αβ, the kinases required for NF-κB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-κB and cytokine induction in −/− DCs. Together, TLR signals that activate NF-κB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
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toll like receptor 9 signaling activates nf κb through ifn regulatory factor 8 ifn Consensus Sequence binding protein in dendritic cells
Journal of Immunology, 2004Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Hee Jeong Kong, Akira Nishiyama, Dennis M Klinman, Ken Ishii, Keiko OzatoAbstract:Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-kappaB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN Consensus Sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8(-/-) mice were unresponsive to CpG and failed to induce TNF-alpha and IL-6, targets of NF-kappaB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8(-/-) DCs in response to LPS that signals through TLR4. IRF-8(-/-) DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-kappaB in -/- cells. This was due to the selective inability of -/- DCs to activate I-kappaB kinase alphabeta, the kinases required for NF-kappaB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-kappaB and cytokine induction in -/- DCs. Together, TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
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cutting edge ifn Consensus Sequence binding protein ifn regulatory factor 8 drives the development of type i ifn producing plasmacytoid dendritic cells
Journal of Immunology, 2003Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Keiko OzatoAbstract:IFN Consensus Sequence binding protein (ICSBP/IFN regulatory factor 8) is a hematopoietic cell-specific transcription factor essential for the generation of CD8α+ dendritic cells (DCs). We found that ICSBP−/− mice lack B220+CD11b− plasmacytoid DCs (pDCs) in addition to CD8α+ DCs. Although ICSBP−/− mice have B220−CD11b+ myeloid DCs (mDCs), they fail to mature upon Toll-like receptor signaling. Accordingly, ICSBP−/− bone marrow progenitor cells were Tefective in generating pDCs in the fms-like tyrosine kinase 3 ligand-based culture system and mDCs generated in this system were defective in maturation. We demonstrate that introduction of ICSBP rescues the development of pDCs from −/− bone marrow progenitors. ICSBP also restored the ability of both pDCs and mDCs to mature after Toll-like receptor signals. ICSBP-restored DCs produced IFN-α and IL-12p40 in a DC subset-selective manner with the amounts comparable to those by +/+ DCs. Together, ICSBP is essential for early pDC development and final maturation of both pDCs and mDCs.
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an ifn γ inducible transcription factor ifn Consensus Sequence binding protein icsbp stimulates il 12 p40 expression in macrophages
Journal of Immunology, 2000Co-Authors: Iming Wang, Cristina Contursi, Atsuko Masumi, Giorgio Trinchieri, Keiko OzatoAbstract:IL-12 is a cytokine that links innate and adaptive immunity. Its subunit p40 is induced in macrophages following IFN-γ/LPS stimulation. Here we studied the role for IFN Consensus Sequence binding protein (ICSBP), an IFN-γ/LPS-inducible transcription factor of the IFN regulatory factor (IRF) family in IL-12 p40 transcription. Macrophage-like cells established from ICSBP−/− mice did not induce IL-12 p40 transcripts, nor stimulated IL-12 p40 promoter activity after IFN-γ/LPS stimulation, although induction of other inducible genes was normal in these cells. Transfection of ICSBP led to a marked induction of both human and mouse IL-12 p40 promoter activities in ICSBP+/+ and ICSBP−/− cells, even in the absence of IFN-γ/LPS stimulation. Whereas IRF-1 alone was without effect, synergistic enhancement of promoter activity was observed following cotransfection of ICSBP and IRF-1. Deletion analysis of the human promoter indicated that the Ets site, known to be important for activation by IFN-γ/LPS, also plays a role in the ICSBP activation of IL-12 p40. A DNA affinity binding assay revealed that endogenous ICSBP is recruited to the Ets site through protein-protein interaction. Last, transfection of ISCBP alone led to induction of the endogenous IL-12 p40 mRNA in the absence of IFN-γ and LPS. Taken together, our results show that ICSBP induced by IFN-γ/LPS, acts as a principal activator of IL-12p40 transcription in macrophages.
Tomohiko Tamura - One of the best experts on this subject based on the ideXlab platform.
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synergistic activation of interleukin 12 p35 gene transcription by interferon regulatory factor 1 and interferon Consensus Sequence binding protein
Journal of Biological Chemistry, 2004Co-Authors: Jianguo Liu, Tomohiko Tamura, Xiuqin Guan, Keiko OzatoAbstract:Interferon regulatory factor-1 (IRF-1) and interferon Consensus Sequence-binding protein (ICSBP or IRF-8) are two members of the IRF family of transcription factors that play critical roles in interferon signaling in a wide range of host responses to infection and malignancy. Interleukin-12 (IL-12) is a key factor in the induction of innate resistance and generation of T helper type 1 cells and cytotoxic T lymphocytes. In this work, we find that ICSBP-deficient macrophages are highly defective in the production of IL-12. The defect is also observed at the level of IL-12 p40 and p35 mRNA expression. Transcriptional analyses revealed that ICSBP is a potent activator of the IL-12 p35 gene. It acts through a site localized to -226 to -219, named ICSBP-response element (ICSBP-RE), in the human IL-12 p35 promoter through physical association with IRF-1 both in vitro and in vivo. Co-expression of ICSBP and IRF-1 synergistically stimulates the IL-12 p35 promoter activity. Mutations at the ICSBP-RE results in the loss of protein binding as well as transcriptional activation by ICSBP alone or together with IRF-1. This study provides novel mechanistic information on how signals initiated during innate and adaptive immune responses synergize to yield greater IL-12 production and sustained cellular immunity.
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toll like receptor 9 signaling activates nf κb through ifn regulatory factor 8 ifn Consensus Sequence binding protein in dendritic cells
Journal of Immunology, 2004Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Hee Jeong Kong, Akira Nishiyama, Ken J Ishii, Dennis M Klinman, Keiko OzatoAbstract:Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-κB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN Consensus Sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8−/− mice were unresponsive to CpG and failed to induce TNF-α and IL-6, targets of NF-κB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8−/− DCs in response to LPS that signals through TLR4. IRF-8−/− DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-κB in −/− cells. This was due to the selective inability of −/− DCs to activate I-κB kinase αβ, the kinases required for NF-κB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-κB and cytokine induction in −/− DCs. Together, TLR signals that activate NF-κB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
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toll like receptor 9 signaling activates nf κb through ifn regulatory factor 8 ifn Consensus Sequence binding protein in dendritic cells
Journal of Immunology, 2004Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Hee Jeong Kong, Akira Nishiyama, Dennis M Klinman, Ken Ishii, Keiko OzatoAbstract:Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-kappaB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN Consensus Sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8(-/-) mice were unresponsive to CpG and failed to induce TNF-alpha and IL-6, targets of NF-kappaB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8(-/-) DCs in response to LPS that signals through TLR4. IRF-8(-/-) DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-kappaB in -/- cells. This was due to the selective inability of -/- DCs to activate I-kappaB kinase alphabeta, the kinases required for NF-kappaB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-kappaB and cytokine induction in -/- DCs. Together, TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
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cutting edge ifn Consensus Sequence binding protein ifn regulatory factor 8 drives the development of type i ifn producing plasmacytoid dendritic cells
Journal of Immunology, 2003Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Keiko OzatoAbstract:IFN Consensus Sequence binding protein (ICSBP/IFN regulatory factor 8) is a hematopoietic cell-specific transcription factor essential for the generation of CD8α+ dendritic cells (DCs). We found that ICSBP−/− mice lack B220+CD11b− plasmacytoid DCs (pDCs) in addition to CD8α+ DCs. Although ICSBP−/− mice have B220−CD11b+ myeloid DCs (mDCs), they fail to mature upon Toll-like receptor signaling. Accordingly, ICSBP−/− bone marrow progenitor cells were Tefective in generating pDCs in the fms-like tyrosine kinase 3 ligand-based culture system and mDCs generated in this system were defective in maturation. We demonstrate that introduction of ICSBP rescues the development of pDCs from −/− bone marrow progenitors. ICSBP also restored the ability of both pDCs and mDCs to mature after Toll-like receptor signals. ICSBP-restored DCs produced IFN-α and IL-12p40 in a DC subset-selective manner with the amounts comparable to those by +/+ DCs. Together, ICSBP is essential for early pDC development and final maturation of both pDCs and mDCs.
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ifn Consensus Sequence binding protein ifn regulatory factor 8 guides bone marrow progenitor cells toward the macrophage lineage
Journal of Immunology, 2002Co-Authors: Hideki Tsujimura, Tokiko Nagamurainoue, Tomohiko TamuraAbstract:IFN Consensus Sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in myeloid cell development, lineage marker-negative (Lin−) bone marrow progenitor cells were purified from ICSBP+/+ and ICSBP−/− mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin− progenitor cells, and its levels were markedly increased by IFN-γ. The colony-forming potential of ICSBP−/− progenitor cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-γ inhibited colony formation, while promoting macrophage maturation in ICSBP+/+ cells. In contrast, the effects of IFN-γ were completely absent in ICSBP−/− progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in −/− progenitor cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in myeloid cell development by controlling lineage selection and is indispensable for IFN-γ-dependent modulation of progenitor cell maturation.
Hideki Tsujimura - One of the best experts on this subject based on the ideXlab platform.
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toll like receptor 9 signaling activates nf κb through ifn regulatory factor 8 ifn Consensus Sequence binding protein in dendritic cells
Journal of Immunology, 2004Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Hee Jeong Kong, Akira Nishiyama, Ken J Ishii, Dennis M Klinman, Keiko OzatoAbstract:Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-κB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN Consensus Sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8−/− mice were unresponsive to CpG and failed to induce TNF-α and IL-6, targets of NF-κB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8−/− DCs in response to LPS that signals through TLR4. IRF-8−/− DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-κB in −/− cells. This was due to the selective inability of −/− DCs to activate I-κB kinase αβ, the kinases required for NF-κB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-κB and cytokine induction in −/− DCs. Together, TLR signals that activate NF-κB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
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toll like receptor 9 signaling activates nf κb through ifn regulatory factor 8 ifn Consensus Sequence binding protein in dendritic cells
Journal of Immunology, 2004Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Hee Jeong Kong, Akira Nishiyama, Dennis M Klinman, Ken Ishii, Keiko OzatoAbstract:Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-kappaB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN Consensus Sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8(-/-) mice were unresponsive to CpG and failed to induce TNF-alpha and IL-6, targets of NF-kappaB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8(-/-) DCs in response to LPS that signals through TLR4. IRF-8(-/-) DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-kappaB in -/- cells. This was due to the selective inability of -/- DCs to activate I-kappaB kinase alphabeta, the kinases required for NF-kappaB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-kappaB and cytokine induction in -/- DCs. Together, TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
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cutting edge ifn Consensus Sequence binding protein ifn regulatory factor 8 drives the development of type i ifn producing plasmacytoid dendritic cells
Journal of Immunology, 2003Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Keiko OzatoAbstract:IFN Consensus Sequence binding protein (ICSBP/IFN regulatory factor 8) is a hematopoietic cell-specific transcription factor essential for the generation of CD8α+ dendritic cells (DCs). We found that ICSBP−/− mice lack B220+CD11b− plasmacytoid DCs (pDCs) in addition to CD8α+ DCs. Although ICSBP−/− mice have B220−CD11b+ myeloid DCs (mDCs), they fail to mature upon Toll-like receptor signaling. Accordingly, ICSBP−/− bone marrow progenitor cells were Tefective in generating pDCs in the fms-like tyrosine kinase 3 ligand-based culture system and mDCs generated in this system were defective in maturation. We demonstrate that introduction of ICSBP rescues the development of pDCs from −/− bone marrow progenitors. ICSBP also restored the ability of both pDCs and mDCs to mature after Toll-like receptor signals. ICSBP-restored DCs produced IFN-α and IL-12p40 in a DC subset-selective manner with the amounts comparable to those by +/+ DCs. Together, ICSBP is essential for early pDC development and final maturation of both pDCs and mDCs.
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ifn Consensus Sequence binding protein ifn regulatory factor 8 guides bone marrow progenitor cells toward the macrophage lineage
Journal of Immunology, 2002Co-Authors: Hideki Tsujimura, Tokiko Nagamurainoue, Tomohiko TamuraAbstract:IFN Consensus Sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in myeloid cell development, lineage marker-negative (Lin−) bone marrow progenitor cells were purified from ICSBP+/+ and ICSBP−/− mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin− progenitor cells, and its levels were markedly increased by IFN-γ. The colony-forming potential of ICSBP−/− progenitor cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-γ inhibited colony formation, while promoting macrophage maturation in ICSBP+/+ cells. In contrast, the effects of IFN-γ were completely absent in ICSBP−/− progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in −/− progenitor cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in myeloid cell development by controlling lineage selection and is indispensable for IFN-γ-dependent modulation of progenitor cell maturation.
Elizabeth A. Eklund - One of the best experts on this subject based on the ideXlab platform.
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the interferon Consensus Sequence binding protein icsbp irf8 is required for termination of emergency granulopoiesis
Journal of Biological Chemistry, 2016Co-Authors: Weiqi Huang, Leonidas C Platanias, Ling Bei, Elizabeth Hjort, Elizabeth A. EklundAbstract:Emergency granulopoiesis occurs in response to infectious or inflammatory challenge and is a component of the innate immune response. Some molecular events involved in initiating emergency granulopoiesis are known, but termination of this process is less well defined. In this study, we found that the interferon Consensus Sequence binding protein (Icsbp/Irf8) was required to terminate emergency granulopoiesis. Icsbp is an interferon regulatory transcription factor with leukemia suppressor activity. Expression of Icsbp is decreased in chronic myeloid leukemia, and Icsbp(-/-) mice exhibit progressive granulocytosis with evolution to blast crisis, similar to the course of human chronic myeloid leukemia. In this study, we found aberrantly sustained granulocyte production in Icsbp(-/-) mice after stimulation of an emergency granulopoiesis response. Icsbp represses transcription of the genes encoding Fas-associated phosphatase 1 (Fap1) and growth arrest-specific 2 (Gas2) and activates genes encoding Fanconi C and F. After stimulation of emergency granulopoiesis, we found increased and sustained expression of Fap1 and Gas2 in bone marrow myeloid progenitor cells from Icsbp(-/-) mice in comparison with the wild type. This was associated with resistance to Fas-induced apoptosis and increased β-catenin activity in these cells. We also found that repeated episodes of emergency granulopoiesis accelerated progression to acute myeloid leukemia in Icsbp(-/-) mice. This was associated with impaired Fanconi C and F expression and increased sensitivity to DNA damage in bone marrow myeloid progenitors. Our results suggest that impaired Icsbp expression enhances leukemogenesis by deregulating processes that normally limit granulocyte expansion during the innate immune response.
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interferon Consensus Sequence binding protein icsbp decreases β catenin activity in myeloid cells by repressing gas2 transcription
Molecular and Cellular Biology, 2010Co-Authors: Weiqi Huang, Leonidas C Platanias, Gurveen Saberwal, Elizabeth Horvath, Wei Zhou, Iwona M Konieczna, Efstratios Katsoulidis, Elizabeth A. EklundAbstract:The interferon Consensus Sequence binding protein (ICSBP) is an interferon regulatory transcription factor, also referred to as IRF8. ICSBP acts as a suppressor of myeloid leukemia, although few target genes explaining this effect have been identified. In the current studies, we identified the gene encoding growth arrest specific 2 (GAS2) as an ICSBP target gene relevant to leukemia suppression. We find that ICSBP, Tel, and histone deacetylase 3 (HDAC3) bind to a cis element in the GAS2 promoter and repress transcription in myeloid progenitor cells. Gas2 inhibits calpain protease activity, and beta-catenin is a calpain substrate in these cells. Consistent with this, ICSBP decreases beta-catenin protein and activity in a Gas2- and calpain-dependent manner. Conversely, decreased ICSBP expression increases beta-catenin protein and activity by the same mechanism. This is of interest, because decreased ICSBP expression and increased beta-catenin activity are associated with poor prognosis and blast crisis in chronic myeloid leukemia (CML). We find that the expression of Bcr/abl (the CML oncoprotein) increases Gas2 expression in an ICSBP-dependent manner. This results in decreased calpain activity and a consequent increase in beta-catenin activity in Bcr/abl-positive (Bcr/abl(+)) cells. Therefore, these studies have identified a Gas2/calpain-dependent mechanism by which ICSBP influences beta-catenin activity in myeloid leukemia.
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the interferon Consensus Sequence binding protein icsbp irf8 activates transcription of the fancf gene during myeloid differentiation
Journal of Biological Chemistry, 2009Co-Authors: Gurveen Saberwal, Elizabeth Hjort, Chunliu Zhu, Elizabeth Horvath, Elizabeth A. EklundAbstract:The interferon Consensus Sequence binding protein (ICSBP) is an interferon regulatory transcription factor with leukemia-suppressor activity. ICSBP regulates genes that are involved in phagocyte function, proliferation, and apoptosis. In murine models ICSBP deficiency results in a myeloproliferative disorder (MPD) with increased mature neutrophils. Over time this MPD progresses to acute myeloid leukemia (AML), suggesting that ICSBP deficiency is adequate for MPD, but additional genetic lesions are required for AML. The hypothesis of these studies is that dysregulation of key target genes predisposes to disease progression under conditions of decreased ICSBP expression. To investigate this hypothesis, we used chromatin co-immunoprecipitation to identify genes involved the ICSBP-leukemia suppressor effect. In the current studies, we identify the gene encoding Fanconi F (FANCF) as an ICSBP target gene. FancF participates in a repair of cross-linked DNA. We identify a FANCF promoter cis element, which is activated by ICSBP in differentiating myeloid cells. We also determine that DNA cross-link repair is impaired in ICSBP-deficient myeloid cells in a FancF-dependent manner. This effect is observed in differentiating cells, suggesting that ICSBP protects against the genotoxic stress of myelopoiesis. Decreased ICSBP expression is found in human AML and chronic myeloid leukemia during blast crisis (CML-BC). Our studies suggest that ICSBP deficiency may be functionally important for accumulation of chromosomal abnormalities during disease progression in these myeloid malignancies.
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the interferon Consensus Sequence binding protein icsbp irf8 represses ptpn13 gene transcription in differentiating myeloid cells
Journal of Biological Chemistry, 2008Co-Authors: Weiqi Huang, Elizabeth A. Eklund, Chunliu Zhu, Hao Wang, Elizabeth HorvathAbstract:The interferon Consensus Sequence-binding protein (ICSBP/IRF8) is an interferon regulatory factor that is expressed in myeloid and B-cells. ICSBP-deficient mice develop a myeloproliferative disorder characterized by cytokine hypersensitivity and apoptosis resistance. To identify ICSBP target genes involved in these effects, we screened a CpG island microarray with chromatin that co-immunoprecipitated with ICSBP from myeloid cells. Using this technique, we identified PTPN13 as an ICSBP target gene. PTPN13 encodes Fas-associated phosphatase 1 (Fap-1), a ubiquitously expressed protein-tyrosine phosphatase. This was of interest because interaction of Fap-1 with Fas results in Fas dephosphorylation and inhibition of Fas-induced apoptosis. In this study, we found that ICSBP influenced Fas-induced apoptosis in a Fap-1-dependent manner. We also found that ICSBP interacted with a cis element in the proximal PTPN13 promoter and repressed transcription. This interaction increased during myeloid differentiation and was regulated by phosphorylation of conserved tyrosine residues in the interferon regulatory factor domain of ICSBP. ICSBP deficiency was present in human myeloid malignancies, including chronic myeloid leukemia. Therefore, these studies identified a mechanism for increased survival of mature myeloid cells in the ICSBP-deficient murine model and in human myeloid malignancies with decreased ICSBP expression.
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the interferon Consensus Sequence binding protein activates transcription of the gene encoding neurofibromin 1
Journal of Biological Chemistry, 2004Co-Authors: Gurveen Saberwal, Leonidas C Platanias, Yu Feng Lu, Elizabeth A. EklundAbstract:Abstract Deficiency of the interferon Consensus Sequence-binding protein (ICSBP) is associated with increased myeloid cell proliferation in response to hematopoietic cytokines. However, previously identified ICSBP target genes do not indicate a mechanism for this “cytokine hypersen-sitivity.” In these studies, we identify the gene encoding neurofibromin 1 (Nf1) as an ICSBP target gene, by chromatin immunoprecipitation. Additionally, we find decreased Nf1 expression in bone marrow-derived myeloid cells from ICSBP–/– mice. Since Nf1 deficiency is also associated with cytokine hypersensitivity, our results suggested that NF1 is a functionally significant ICSBP target gene. Consistent with this, we find that the hyper-sensitivity of ICSBP–/– myeloid cells to granulocyte monocyte colony-stimulating factor (GM-CSF) is reversed by expression of the Nf1 GAP-related domain. We also find that treatment of ICSBP-deficient myeloid cells with monocyte colony-stimulating factor (M-CSF) results in sustained Ras activation, ERK phosphorylation, and proliferation associated with impaired Nf1 expression. These M-CSF effects are reversed by ICSBP expression in ICSBP–/– cells. Consistent with this, we find that ICSBP activates the NF1 promoter in myeloid cell line transfectants and identify an ICSBP-binding NF1 cis element. Therefore, the absence of ICSBP leads to Nf1 deficiency, impairing down-regulation of Ras activation by GM-CSF or M-CSF. These results suggest that one mechanism of increased myeloid proliferation, in ICSBP-deficient cells, is decreased NF1 gene transcription. This novel ICSBP function provides insight into regulation of myelopoiesis under normal conditions and in myeloproliferative disorders.
Benzion Levi - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation events modulate the ability of interferon Consensus Sequence binding protein to interact with interferon regulatory factors and to bind dna
Journal of Biological Chemistry, 1997Co-Authors: Rakefet Sharf, Keiko Ozato, David Meraro, Aviva Azriel, Angela M Thornton, Emanuel F Petricoin, Andrew C Larner, Fred Schaper, Hansjoerg Hauser, Benzion LeviAbstract:Abstract Two families of transcription factors mediate interferon (IFN) signaling. The first family, signal transducers and activators of transcription (STATs), is activated within minutes of IFN treatment. Specific phosphorylation events lead to their translocation to the nucleus, formation of transcriptional complexes, and the induction of the second family of transcription factors termed interferon regulatory factors (IRFs). Interferon Consensus Sequence binding protein (ICSBP) is a member of IRF family that is expressed only in cells of the immune system and acts as a transcriptional repressor. ICSBP binds DNA through the association with other transcription factors such as IRF-1 or IRF-2. In this communication, the domain that is involved in protein-protein interactions was mapped to the carboxyl terminus of ICSBP. This domain is also important for mediating ICSBP-repressing activity. In vitro studies demonstrated that direct binding of ICSBP to DNA is prevented by tyrosine (Tyr) phosphorylation. Yet, Tyr-phosphorylated ICSBP can bind target DNA only through the association with IRF-2 and IRF-1. This type of phosphorylation is essential for the formation of heterocomplexes. Tyr-phosphorylated ICSBP and IRF-2 are detected in expressing cells constitutively, and Tyr-phosphorylated IRF-1 is induced by IFN-γ. These results strongly suggest that like the STATs, the IRFs are also modulated by Tyr phosphorylation that affects their biological activities.
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functional domain analysis of interferon Consensus Sequence binding protein icsbp and its association with interferon regulatory factors
Journal of Biological Chemistry, 1995Co-Authors: Rakefet Sharf, Aviva Azriel, Flavio Lejbkowicz, Sigal Winograd, Rachel Ehrlich, Benzion LeviAbstract:Abstract Interferon Consensus Sequence binding protein (ICSBP) is a member of the interferon regulatory factor (IRF) family of proteins that include IRF-1, IRF-2, and ISGF3 which share Sequence similarity at the putative DNA binding domain (DBD). ICSBP is expressed exclusively in cells of the immune system and acts as a repressor of interferon Consensus Sequence (ICS) containing promoters that can be alleviated by interferons. In this communication, we have searched for functional domains of ICSBP by dissecting the DBD from the repression activity. The putative DBD of ICSBP (amino acids 1-121) when fused in frame to the transcriptional activation domain of the herpes simplex VP16 (ICSBP-VP16) is a very strong activator of ICS-containing promoters. In addition, ICSBP-VP16 fusion construct transfected into adenovirus (Ad) 12 transformed cells enabled cell surface expression of major histocompatibility complex class I antigens as did treatment with interferon. On the other hand, the DBD of the yeast transcriptional activator GAL4 was fused in frame to a truncated ICSBP in which the DBD was impaired resulting in a chimeric construct GAL4-ICSBP. This construct is capable of repressing promoters containing GAL4 binding sites. Thus, ICSBP contains at least two independent domains: a DBD and a transcriptional repressor domain. Furthermore, we have tested possible interactions between ICSBP and IRFs. The chimeric construct GAL4-ICSBP inhibited the stimulated effect of IRF-1 on a reporter gene, implying for a possible interaction between IRF-1 and ICSBP. Electromobility shift assays, demonstrated that ICSBP can associate with IRF-2 or IRF-1 in vitro as well as in vivo. Thus, ICSBP contains a third functional domain that enables the association with IRFs. These associations are probably important for the fine balance between positive and negative regulators involved in the interferon-mediated signal transduction pathways in cells of the immune system.
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human interferon Consensus Sequence binding protein is a negative regulator of enhancer elements common to interferon inducible genes
Journal of Biological Chemistry, 1992Co-Authors: A Weisz, P H Driggers, Rakefet Sharf, P Marx, E Appella, K Ozato, Benzion LeviAbstract:Abstract The promoter regions of many interferon-inducible genes share a short DNA Sequence motif, termed the interferon Consensus Sequence (ICS) to which several regulatory proteins bind. A murine cDNA which encodes an ICS binding protein has been reported (M-ICSBP). The cloning of the human homologue of ICSBP (H-ICSBP) is described. H-ICSBP shares high Sequence homology with its murine cognate. The derived Sequence of H-ICSBP reveals restricted homology within the first 120 amino acids to three other interferon regulatory factors, IRF-1, IRF-2, and ISGF3 gamma. Truncated ICSBP lacking the first 33 amino-terminal amino acids fails to bind to the ICS, indicating that at least part of the DNA binding domain is located within the well conserved amino terminus. H-ICSBP is expressed exclusively in cell lines of hematopoietic origin. The results of transient transfection assays carried out either in hematopoietic or nonhematopoietic cells suggest that ICSBP acts as a negative regulatory factor on ICS-containing promoters. Furthermore, either interferon-gamma (IFN-gamma) or IFN-beta can alleviate the repression mediated by ICSBP. Therefore, ICSBP may be involved in maintaining submaximal transcriptional activity of IFN-inducible genes in hematopoietic cells. IFN treatment would then alleviate repression allowing maximal transcriptional activity of these genes.