<b>Regulation of IFN‐α/β genes: evidence for a dual function of the transcription factor complex ISGF3 in the production and action of IFN‐α/β</b>

Harada, Hisashi; Matsumoto, Masahito; Sato, Mitsuharu; Kashiwazaki, Yasuo; Kimura, Tohru; Kitagawa, Motoo; Yokochi, Taeko; Tan, Rosemary; Takasugi, Tomohiro; Kadokawa, Yuzo; Schindler, Christian; Schreiber, Robert D.; Noguchi, Shigeru; Taniguchi, Tadatsugu

doi:10.1046/j.1365-2443.1996.870287.x

Cited by 87 publications

(71 citation statements)

References 38 publications

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“…These findings are underscored by our data demonstrating that knockdown of NLRC5 significantly impairs induction of these target genes in the context of CMV infection. IFN-a transcriptional regulation has been shown to be dependent on JAK/STAT signaling via the IFN-stimulated gene factor 3 transcription factor complex (36). PRKRIR encodes for a protein that was first identified as a regulator of P58(IPK), a cellular inhibitor of the RNAdependent protein kinase (37).…”

Section: Discussionmentioning

confidence: 99%

The Nucleotide-Binding Oligomerization Domain-Like Receptor NLRC5 Is Involved in IFN-Dependent Antiviral Immune Responses

Kuenzel¹,

Till²,

Winkler

et al. 2010

The Journal of Immunology

180

187

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Nucleotide-binding oligomerization domain-like receptors (NLRs) are a group of intracellular proteins that mediate recognition of pathogen-associated molecular patterns or other cytosolic danger signals. Mutations in NLR genes have been linked to a variety of inflammatory diseases, underscoring their pivotal role in host defense and immunity. This report describes the genomic organization and regulation of the human NLR family member NLRC5 and aspects of cellular function of the encoded protein. We have analyzed the tissue-specific expression of NLRC5 and have characterized regulatory elements in the NLRC5 promoter region that are responsive to IFN-γ. We show that NLRC5 is upregulated in human fibroblasts postinfection with CMV and demonstrate the role of a JAK/STAT-mediated autocrine signaling loop involving IFN-γ. We demonstrate that overexpression and enforced oligomerization of NLRC5 protein results in activation of the IFN-responsive regulatory promoter elements IFN-γ activation sequence and IFN-specific response element and upregulation of antiviral target genes (e.g., IFN-α, OAS1, and PRKRIR). Finally, we demonstrate the effect of small interfering RNA-mediated knockdown of NLRC5 on a target gene level in the context of viral infection. We conclude that NLRC5 may represent a molecular switch of IFN-γ activation sequence/IFN-specific response element signaling pathways contributing to antiviral defense mechanisms.

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Section: Discussionmentioning

confidence: 99%

The Nucleotide-Binding Oligomerization Domain-Like Receptor NLRC5 Is Involved in IFN-Dependent Antiviral Immune Responses

Kuenzel¹,

Till²,

Winkler

et al. 2010

The Journal of Immunology

180

187

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“…Induction of ISREcontaining genes by either IFNs or both IFNs and virus through different pathways requires different IRF family members: the IFN signaling pathway involves IRF9, and the IFNindependent pathway activated by virus infection requires IRF3 and IRF7. The biological significance of the distinct pathways is obscure, but they do not perform redundant functions, may complement each other for an efficient antiviral response (30,57,58), and may reflect distinct requirements at different stages during virus infection. In addition, in contrast to IRF3, which is constitutively expressed in all cell types and is inducible neither by IFNs nor upon virus infection (59), IRF7 is not constitutively expressed in most cell types.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Transcriptional Activity of the IRF7 Promoter by a Pathway Independent of Interferon Signaling

Ning

Huye

Pagano

2005

Journal of Biological Chemistry

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“…by guest www.bloodjournal.org From B lymphoblasts, MEFs, and patient LDBMCs, is of particular interest because it is the only protein of the IRF family known to complex with STAT molecules. 42 ISGF3␥ exerts its transcriptional activation only in conjunction with STAT1 and STAT2 43 and plays a crucial role in the regulation of IFN-␤ gene expression, [44][45][46] a finding of relevance because some researchers have suggested that the induced expression of IFN-␤ is required for the hematopoietic suppressive effects of IFN␥. 47 IRF-1 is required for carrying out the apoptotic effects of IFN␥ signaling.…”

Section: Discussionmentioning

confidence: 99%

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

Fagerlie

Diaz

Christianson

et al. 2001

Blood

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IntroductionFanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure, multiple congenital anomalies, and a high incidence of acute myelogenous leukemia. [1][2][3][4] Cells from FA patients are hypersensitive to the effects of DNA cross-linking agents, such as mitomycin C and diepoxybutane. 5,6 The disorder is genetically heterogeneous, with at least 7 different complementation groups. 7,8 The genes corresponding to group A (FANCA), C (FANCC), E (FANCE), F (FANCF), and G (FANCG) have been cloned. [9][10][11][12][13] Fanconi gene sequences show no significant homology to any known genes, and the functions of their gene products are unknown. 14,15 Hematopoietic precursor cells from children with FA of the C complementation group (FA-C) are excessively apoptotic and hypersensitive to a variety of cytokines known to induce apoptosis, including interferon ␥ (IFN␥). IFN␥ is a cytokine involved in host defense against viral infections and regulation of cell growth. 16 IFN␥ clearly plays a role in hematopoietic suppression and has been implicated in the pathogenesis of acquired aplastic anemia. [16][17][18][19][20][21][22] Cells with inactivating FANCC mutations are hypersensitive to the apoptotic effects of IFN␥, an effect that depends in part on an intact fas/fas-ligand pathway. [23][24][25][26] Specifically, exposure to low doses of IFN␥ in vitro primes a substantial fraction of FA-C progenitor cells to undergo apoptosis after subsequent exposure to fas ligand. Such doses of IFN␥ have no effect on normal hematopoietic progenitor cells. 23,24 Because of the influence of IFN␥ on the fas pathway, we sought to determine whether other IFN␥-inducible genes are hyperactive in FA-C cells. We carried out studies designed to analyze expression of IFN␥-inducible genes known to promote apoptosis and/or mitogenic inhibition in hematopoietic progenitor cells. We describe here studies revealing that the transactivators interferon regulatory factor-1 (IRF-1) and IFNstimulated gene factor 3 gamma subunit (ISGF3␥) and the cyclindependent kinase (cdk) inhibitor p21 WAF1 are expressed at constitutively higher levels in FA-C B lymphoblasts, low-density bone marrow cells (LDBMCs), and murine embryonic fibroblasts (MEFs), compared with cells expressing a normal FANCC. However, these proteins are expressed at normal levels in mature mutant fibroblasts, suggesting some degree of tissue or developmental stage specificity of FANCC function in control of these genes.IFN␥ exerts its effects, at least in part, through the Jak/signal transducer and activator of transcription (STAT) signaling pathway, 27,28 However, FA-C cells are defective in their ability to properly activate STAT1. 29 We show here that up-regulation of IFN␥-inducible genes occurs precisely in those cell types that fail to properly activate STAT1. For this reason, we hypothesized that loss of a STAT1-inducible transcriptional repressor may result in up-regulation of IFN␥-inducible genes in FA-C cells. Indeed, we found expression of the...

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Regulation of IFN‐α/β genes: evidence for a dual function of the transcription factor complex ISGF3 in the production and action of IFN‐α/β

Cited by 87 publications

References 38 publications

The Nucleotide-Binding Oligomerization Domain-Like Receptor NLRC5 Is Involved in IFN-Dependent Antiviral Immune Responses

The Nucleotide-Binding Oligomerization Domain-Like Receptor NLRC5 Is Involved in IFN-Dependent Antiviral Immune Responses

Regulation of the Transcriptional Activity of the IRF7 Promoter by a Pathway Independent of Interferon Signaling

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

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