IRF-7, a New Interferon Regulatory Factor Associated with Epstein-Barr Virus Latency

Zhang, Luwen; Pagano, Joseph S.

doi:10.1128/mcb.17.10.5748

Cited by 239 publications

(294 citation statements)

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“…The gene structure of mandarin fish IRF-7 was different from the only known vertebrate IRF-7, i.e. human IRF-7 gene structure, which has 9 exons and 8 introns (Zhang and Pagano, 1997;Au et al, 1998). The mandarin fish IRF-7 contains a serine-rich domain located in the C-terminal region, just as its homologue in mammals (Au et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Gene structure and transcription of IRF-1 and IRF-7 in the mandarin fish Siniperca chuatsi

Sun

Chang

Song

et al. 2007

Veterinary Immunology and Immunopathology

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Section: Discussionmentioning

confidence: 99%

Gene structure and transcription of IRF-1 and IRF-7 in the mandarin fish Siniperca chuatsi

Sun

Chang

Song

et al. 2007

Veterinary Immunology and Immunopathology

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“…Importantly, we have found that Notch activation in keratinocytes causes selective suppression of some interferon-responsive genes, while inducing others (Supplementary Table 2), pointing to the existence of a novel mechanism for the fine tuning of the interferon response, which may be of particular significance for modulation of growth-differentiation control as opposed to the antiviral function. Several of the interferon-responsive genes under negative Notch control in keratinocytes have been previously implicated in positive growth control, apoptosis, and/or tumorigenesis (e.g., see Ghosh et al 2001;Carpten et al 2002;Wasylyk et al 2002;Zhang and Pagano 2002), with an impact that is likely to extend to keratinocytes. We note in particular the down-modulation of Sp100, a key component of nuclear bodies involved in chromatin control (Moller et al 2003), which parallels the opposite up-regulation of PML, another nuclear body component, in cells with loss of p63 expression (Bernassola et al 2005;Keyes et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Besides NF-B-binding sites, both mouse and human ⌬Np63 promoters contain several interferon-responsive elements, with a potentially significant similarity with the ␤-interferon enhancer, where a synergistic multiprotein complex is formed (Thanos and Maniatis 1995) by NF-B subunits and IRF3/IRF7 proteins, two key downstream mediators of the interferon response (Servant et al 2002;Zhang and Pagano 2002). Consistent with an involvement of this latter pathway, overexpression of IRF7, while by itself not increasing p63 expression, was sufficient to block the Notch-dependent suppression.…”

Section: Discussionmentioning

confidence: 99%

“…Similar results were obtained in two other independent experiments. et al 1999), or the full-length IRF7 protein, which, as mentioned, is a key downstream mediator of the interferon response (Zhang and Pagano 2002;Honda et al 2005) and functionally overlaps with IRF3 (Servant et al 2002). Expression of stabilized "super-repressor" I B-␣ resulted in a substantial induction of p63 expression, indicating that the NF-B pathway functions as a negative regulator of p63 already in keratinocytes under basal growing conditions (Fig.…”

Section: Notch Activation Suppresses P63 Expression Through Negative mentioning

confidence: 99%

“…Furthermore, the specific set of interferon-responsive genes that were found to be downmodulated in the mouse and human genes was different. Among the suppressed genes in human cells were the ones for IRF7, a key regulator of the interferon-dependent transcription cascade with oncogenic potential (Zhang and Pagano 2002;Honda et al 2005), and Sp100, an essential component of nuclear bodies (NBs) ( Fig. 3D; Moller et al 2003), while in the mouse cells down-modulation was observed for IRF3, which physically interacts and functionally overlaps with IRF7 (Servant et al 2002), and IKK , a key kinase that positively regulates the interferon response ( Fig.…”

Section: Notch Activation Suppresses P63 Expression Through Negative mentioning

confidence: 99%

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Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

341

411

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Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Normal tissue homeostasis is determined by a complex interplay between developmental signals and other cell regulatory pathways. Notch cell surface receptors and their ligands belonging to the Delta and Serrate/Jagged families play a crucial role in cell fate determination and differentiation, functioning in a cell-and context-specific manner (Artavanis-Tsakonas et al. 1999). In mammalian cells, Notch activation is generally thought to maintain stem cell potential and inhibit differentiation, thereby promoting carcinogenesis (Artavanis-Tsakonas et al. 1999). However, in specific cell types such as keratinocytes, increased Notch activity causes exit from the cell cycle and commitment to differentiation (Lowell et al. 2000;Rangarajan et al. 2001;Nickoloff et al. 2002), whereas down-modulation or loss of Notch1 function promotes carcinogenesis (Talora et al. 2002;Nicolas et al. 2003).In the human epidermis, localized expression of the Notch-ligand Delta in putative "stem cells" has been proposed to induce commitment of neighboring Notch1-expressing keratinocytes to a "transit-amplifying" phenotype, through a negative feedback mechanism of lateral inhibition (Lowell et al. 2000). On the other hand, in both mouse and human epidermis, Jagged 1/2, Notch1, and Notch2 are coexpressed in differentiating keratinocytes of the supra-basal layers, consistent with a positive feedback loop between these molecules that serves to reinforce and synchronize Notch activation with differentiation (Luo et al. 1997;Rangarajan et al. 2001;Nickoloff et al. 2002).The best characterized "canonical" pathway of Notch activation involves proteolytic cleavage and translocation of the cytoplasmic domain of the receptor to the nucleus, where it associates with the DNA-binding protein RBP-J (CBF-1, CSL), converting it from a repressor

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Counter‐regulation mechanism of IL‐4 and IFN‐α signal transduction through cytosolic retention of the pY‐STAT6:pY‐STAT2:p48 complex

Kim¹,

Lee²

2010

Eur J Immunol

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IFN-a and IL-4 induce Th1 and Th2 responses, respectively, and often display antagonistic actions against each other. To elucidate the molecular mechanism of counter-regulation, we have investigated the signal interception by IFN-a and IL-4, employing a human B-cell line Ramos, sensitive to both cytokines. In these cells, IFN-a effectively inhibited IL-4-induced Fc epsilon receptor II (CD23) expression, whereas IL-4 suppressed IFN-amediated IRF7 expression. The counter-regulatory action by IL-4 and IFN-a proceeded with a delayed kinetics requiring 4 h. Notably, IFN-a did not affect the IL-4-induced tyrosine phosphorylation of STAT6, but induced a time-dependent cytoplasmic accumulation of phosphotyrosine(pY)-STAT6 and a corresponding decrease in nuclear pY-STAT6. By confocal analysis and co-immunoprecipitation assays, we demonstrated the colocalization and molecular interaction of IL-4-induced pY-STAT6 with IFN-a-induced pY-STAT2:p48 in the cytosol. In addition, the over-expression of STAT2 or STAT6 induced the concomitant cytosolic accumulation of pY-STAT6 or pY-STAT2, leading to the suppression of IL-4-induced CD23 or IFN-a-induced IRF7 gene expression, respectively. Our data suggest that the signals ensued by IFN-a and IL-4 induce cytoplasmic sequestration of IL-4-activated STAT6 and IFN-a-activated STAT2:p48 in B cells through the formation of pY-STAT6:pY-STAT2:p48 complex, which provides a novel mechanism by which IFN-a and IL-4 cross-regulate their signaling into the nucleus.Keywords: Counter-regulation . Cytosolic retention . IFN-a signaling . IL-4 signaling pY-STAT6:pY-STAT2:p48 complex Supporting Information available online IntroductionIn the innate and the adaptive immune system, cytokines act as key regulators for the activation, proliferation, differentiation, development, and death of immune cells [1,2]. IL-4 is an immunomodulatory cytokine secreted by activated Th2 lymphocytes, basophils, and mast cells [3]. Its pleiotropic functions include the differentiation of Th2 cells, B-cell activation, immunoglobulin isotype switching, the inhibition of Th1 differentiation, and the development of allergic diseases. In hematopoietic cells, responses to IL-4 are mediated by the receptor complex composed of IL-4 receptor (IL-4R) a and common g-chain (gc). Once these receptor chains are heterodimerized upon IL-4 binding, the receptor-associated Jaks (Jak 1/3) are activated, inducing phosphorylation of a tyrosine residue within the cytoplasmic tail of IL-4Ra [3]. The phosphotyrosine (pY) 461 motif generated on the receptor then acts as a docking site to recruit STAT6, leading to the tyrosine phosphorylation of STAT6 by Jaks. Subsequently, phosphorylated STAT6 departs from the receptor, dimerizes, and translocates into the nucleus, where it turns on the expression of IL-4 target genes [3,4]. The IL-4-induced STAT6 activity is shown to be essential for the establishment of distal promoter activity for GATA3 transcription in developing Th2 cells [5]. IFNs are widely expressed cytokines with multiple biological act...

show abstract

IRF-7, a New Interferon Regulatory Factor Associated with Epstein-Barr Virus Latency

Abstract: The Epstein-Barr virus (EBV)BamHI

Cited by 239 publications

References 50 publications

Gene structure and transcription of IRF-1 and IRF-7 in the mandarin fish Siniperca chuatsi

Gene structure and transcription of IRF-1 and IRF-7 in the mandarin fish Siniperca chuatsi

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Counter‐regulation mechanism of IL‐4 and IFN‐α signal transduction through cytosolic retention of the pY‐STAT6:pY‐STAT2:p48 complex

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