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Vera L. Tarakanova - One of the best experts on this subject based on the ideXlab platform.
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Tumor suppressor Interferon Regulatory Factor 1 selectively blocks expression of endogenous retrovirus.
Virology, 2018Co-Authors: K.p. Stoltz, C. N. Jondle, Kirthi Pulakanti, P. A. Sylvester, Raul Urrutia, Sridhar Rao, Vera L. TarakanovaAbstract:Endogenous retroviruses (ERVs) comprise 10% of the genome, with many of these transcriptionally silenced post early embryogenesis. Several stimuli, including exogenous virus infection and cellular transformation can reactivate ERV expression via a poorly understood mechanism. We identified Interferon Regulatory Factor 1 (IRF-1), a tumor suppressor and an antiviral host factor, as a suppressor of ERV expression. IRF-1 decreased expression of a specific mouse ERV in vitro and in vivo. IRF-3, but not IRF-7, also decreased expression of distinct ERV families, suggesting that suppression of ERVs is a relevant biological function of the IRF family. Given the emerging appreciation of the physiological relevance of ERV expression in cancer, IRF-1-mediated suppression of specific ERVs may contribute to the overall tumor suppressor activity of this host factor.
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Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection.
Journal of virology, 2016Co-Authors: Wadzanai P. Mboko, Michaela M. Rekow, Mitchell P. Ledwith, Philip T. Lange, Kaitlin E. Schmitz, Sean Anderson, Vera L. TarakanovaAbstract:Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in >95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon Regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I Interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection. IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I Interferon (IFN) signaling and Interferon Regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.
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Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells
Journal of virology, 2014Co-Authors: Wadzanai P. Mboko, Eric J. Darrah, Bryan C. Mounce, Joseph Emmer, Shailendra B. Patel, Vera L. TarakanovaAbstract:Gammaherpesviruses are ubiquitous pathogens that establish a lifelong infection and are associated with cancer. In spite of the high seroprevalence of infection, the risk factors that predispose the host toward gammaherpesvirus-induced malignancies are still poorly understood. Interferon (IFN) Regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. On the basis of its biology, IRF-1 represents a plausible host factor to attenuate gammaherpesvirus infection and tumorigenesis. In this study, we show that IRF-1 restricts gammaherpesvirus replication in primary macrophages, a physiologically relevant immune cell type. In spite of the known role of IRF-1 in stimulating type I IFN expression, induction of a global type I IFN response was similar in IRF-1-deficient and -proficient macrophages during gammaherpesvirus infection. However, IRF-1 was required for optimal expression of cholesterol-25-hydroxylase, a host enzyme that restricted gammaherpesvirus replication in primary macrophages and contributed to the antiviral effects of IRF-1. In summary, the current study provides an insight into the mechanism by which IRF-1 attenuates gammaherpesvirus replication in primary immune cells, a mechanism that is likely to contribute to the antiviral effects of IRF-1 in other virus systems. IMPORTANCE Interferon Regulatory factor 1 (IRF-1) is a transcription factor that regulates innate and adaptive immune responses and functions as a tumor suppressor. IRF-1 restricts the replication of diverse viruses; however, the mechanisms responsible for the antiviral effects of IRF-1 are still poorly understood. Gammaherpesviruses are ubiquitous pathogens that are associated with the induction of several malignancies. Here we show that IRF-1 expression attenuates gammaherpesvirus replication in primary macrophages, in part by increasing expression of cholesterol-25-hydroxylase (CH25H). CH25H and its product, 25-hydroxycholesterol, restrict replication of diverse virus families. Thus, our findings offer an insight into the mechanism by which IRF-1 attenuates the replication of gammaherpesviruses, a mechanism that is likely to be applicable to other virus systems.
Joonho Choe - One of the best experts on this subject based on the ideXlab platform.
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identification of the dna sequence interacting with kaposi s sarcoma associated herpesvirus viral Interferon Regulatory factor 1
Journal of Virology, 2007Co-Authors: Junsoo Park, Kwi Wan Jeong, Joonho ChoeAbstract:Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma. The open reading frame (K9) of KSHV encodes viral Interferon Regulatory factor 1 (vIRF1), which functions as a repressor of Interferon-mediated signal transduction. The amino-terminal region of vIRF1 displays significant homology to the DNA-binding domain of cellular Interferon Regulatory factors, supporting the theory that the protein interacts with specific DNA sequences. Here, we identify the consensus sequence of vIRF1-binding sites from a pool of random oligonucleotides. Moreover, our data show that vIRF1 interacts with the K3:viral dihydrofolate reductase:viral interleukin 6 promoter region in the KSHV genome.
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Viral Interferon Regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus binds to p53 and represses p53-dependent transcription and apoptosis.
Journal of virology, 2001Co-Authors: Taegun Seo, Junsoo Park, Daeyoup Lee, Sun Gwan Hwang, Joonho ChoeAbstract:Kaposi's sarcoma-associated herpesvirus (KSHV) is related to the development of Kaposi's sarcoma. Open reading frame K9 of KSHV encodes viral Interferon Regulatory factor 1 (vIRF1), which functions as a repressor of Interferon- and IRF1-mediated signal transduction. In addition, vIRF1 acts as an oncogene to induce cellular transformation. Here we show that vIRF1 directly associates with the tumor suppressor p53 and represses its functions. The vIRF1 interaction domains of p53 are the DNA binding domain (amino acids [aa] 100 to 300) and the tetramerization domain (aa 300 to 393). p53 interacts with the central region (aa 152 to 360) of vIRF1. vIRF1 suppresses p53-dependent transcription and deregulates its apoptotic activity. These results suggest that vIRF1 may regulate cellular function by inhibiting p53.
Wadzanai P. Mboko - One of the best experts on this subject based on the ideXlab platform.
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Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection.
Journal of virology, 2016Co-Authors: Wadzanai P. Mboko, Michaela M. Rekow, Mitchell P. Ledwith, Philip T. Lange, Kaitlin E. Schmitz, Sean Anderson, Vera L. TarakanovaAbstract:Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in >95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon Regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I Interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection. IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I Interferon (IFN) signaling and Interferon Regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.
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Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus.
Journal of virology, 2015Co-Authors: Wadzanai P. Mboko, Horatiu Olteanu, Avijit Ray, Gang Xin, Eric J. Darrah, Suresh N. Kumar, Joseph M. Kulinski, Weiguo Cui, Bonnie N. Dittel, Stephen B. GauldAbstract:ABSTRACT Gammaherpesviruses are ubiquitous pathogens that are associated with the development of B cell lymphomas. Gammaherpesviruses employ multiple mechanisms to transiently stimulate a broad, polyclonal germinal center reaction, an inherently mutagenic stage of B cell differentiation that is thought to be the primary target of malignant transformation in virus-driven lymphomagenesis. We found that this gammaherpesvirus-driven germinal center expansion was exaggerated and lost its transient nature in the absence of Interferon-Regulatory factor 1 (IRF-1), a transcription factor with antiviral and tumor suppressor functions. Uncontrolled and persistent expansion of germinal center B cells led to pathological changes in the spleens of chronically infected IRF-1-deficient animals. Additionally, we found decreased IRF-1 expression in cases of human posttransplant lymphoproliferative disorder, a malignant condition associated with gammaherpesvirus infection. The results of our study define an unappreciated role for IRF-1 in B cell biology and provide insight into the potential mechanism of gammaherpesvirus-driven lymphomagenesis. IMPORTANCE Gammaherpesviruses establish lifelong infection in most adults and are associated with B cell lymphomas. While the infection is asymptomatic in many hosts, it is critical to identify individuals who may be at an increased risk of virus-induced cancer. Such identification is currently impossible, as the host risk factors that predispose individuals toward viral lymphomagenesis are poorly understood. The current study identifies Interferon-Regulatory factor 1 (IRF-1) to be one of such candidate host factors. Specifically, we found that IRF-1 enforces long-term suppression of an inherently mutagenic stage of B cell differentiation that gammaherpesviruses are thought to target for transformation. Correspondingly, in the absence of IRF-1, chronic gammaherpesvirus infection induced pathological changes in the spleens of infected animals. Further, we found decreased IRF-1 expression in human gammaherpesvirus-induced B cell malignancies.
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Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells
Journal of virology, 2014Co-Authors: Wadzanai P. Mboko, Eric J. Darrah, Bryan C. Mounce, Joseph Emmer, Shailendra B. Patel, Vera L. TarakanovaAbstract:Gammaherpesviruses are ubiquitous pathogens that establish a lifelong infection and are associated with cancer. In spite of the high seroprevalence of infection, the risk factors that predispose the host toward gammaherpesvirus-induced malignancies are still poorly understood. Interferon (IFN) Regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. On the basis of its biology, IRF-1 represents a plausible host factor to attenuate gammaherpesvirus infection and tumorigenesis. In this study, we show that IRF-1 restricts gammaherpesvirus replication in primary macrophages, a physiologically relevant immune cell type. In spite of the known role of IRF-1 in stimulating type I IFN expression, induction of a global type I IFN response was similar in IRF-1-deficient and -proficient macrophages during gammaherpesvirus infection. However, IRF-1 was required for optimal expression of cholesterol-25-hydroxylase, a host enzyme that restricted gammaherpesvirus replication in primary macrophages and contributed to the antiviral effects of IRF-1. In summary, the current study provides an insight into the mechanism by which IRF-1 attenuates gammaherpesvirus replication in primary immune cells, a mechanism that is likely to contribute to the antiviral effects of IRF-1 in other virus systems. IMPORTANCE Interferon Regulatory factor 1 (IRF-1) is a transcription factor that regulates innate and adaptive immune responses and functions as a tumor suppressor. IRF-1 restricts the replication of diverse viruses; however, the mechanisms responsible for the antiviral effects of IRF-1 are still poorly understood. Gammaherpesviruses are ubiquitous pathogens that are associated with the induction of several malignancies. Here we show that IRF-1 expression attenuates gammaherpesvirus replication in primary macrophages, in part by increasing expression of cholesterol-25-hydroxylase (CH25H). CH25H and its product, 25-hydroxycholesterol, restrict replication of diverse virus families. Thus, our findings offer an insight into the mechanism by which IRF-1 attenuates the replication of gammaherpesviruses, a mechanism that is likely to be applicable to other virus systems.
Hidetsugu Saito - One of the best experts on this subject based on the ideXlab platform.
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Interferon Regulatory factor 1 promoter polymorphism and response to type 1 Interferon.
Journal of Cellular Biochemistry, 2001Co-Authors: Hidetsugu Saito, Shinichiro Tada, Hirotoshi Ebinuma, Kanji Wakabayashi, Tamako Takagi, Yoshimasa Saito, Nobuhiro Nakamoto, Satoshi Kurita, Hiromasa IshiiAbstract:The clinical success of Interferon-treatment has been found to vary in different individuals. To explain this, we hypothesized that responses to type 1 Interferons could be partly determined by Interferon Regulatory Factor-1 gene transcription, because the latter is an important transcription factor in the Interferon system. We demonstrated that the antiproliferative effect of type 1 Interferons on human liver cancer cells correlates with levels of transcription of the Interferon Regulatory Factor-1 gene in parallel with those of p21WAF-1 expression. Here, we investigated whether mutations in the Interferon Regulatory Factor-1 gene cause different responses to type 1 Interferons. DNA from several human liver cancer cell lines and peripheral blood mononuclear cells was investigated. Nucleotide sequences of the Interferon Regulatory Factor-1 gene and polymerase chain reaction products of its upstream region were determined directly and after cloning. The promoter activity of the upstream region of this gene was measured by the luciferase reporter assay. We found 4 point mutations in the upstream (− 1 ∼ − 495) region, and the luciferase promoter assay demonstrated that these mutations did modify promoter activity. Analysis of DNA from healthy volunteers showed that these mutations are single nucleotide polymorphisms. These results suggest that single nucleotide polymorphisms of the Interferon Regulatory Factor-1 promoter contribute, at least in part, to determining responses to type 1 Interferons. J. Cell. Biochem. Suppl. 36: 191–200, 2001. © 2001 Wiley-Liss, Inc.
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Growth Inhibition of Hepatoma Cells by Type 1 Interferons: Modification by Mutations in the Interferon Regulatory Factor-1 Gene
Trends in Gastroenterology and Hepatology, 2001Co-Authors: Hidetsugu Saito, Shinichiro Tada, Kanji Wakabayashi, Tamako Takagi, Nobuhiro Nakamoto, Satoshi Kurita, Hlromasa IshiiAbstract:Interferon Regulatory Factor-1 is an important transcription factor in the Interferon system. We have demonstrated that the growth inhibitory effect of type 1 Interferons on human hepatoma cells correlates with levels of transcription of the Interferon Regulatory Factor-1 gene. In this study we investigated whether mutations in this gene cause different responses to type 1 Interferons. DNA from several human hepatoma cell lines was investigated, and nucleotide sequences of the Interferon Regulatory Factor-1 gene were determined. Several point mutations were detected in intron 8 of the gene, and one was found to cause deletion of BamHI cleavage sites. We found several point mutations in the upstream region of the Interferon Regulatory Factor-1 exon 1, and the luciferase promoter assay demonstrated that these mutations modified its promoter activity. These results suggest that polymorphisms of the Interferon Regulatory Factor-1 gene partially contribute to determining the response of cancer cells to growth inhibitory effect of type 1 Interferons.
Yuqing E. Chen - One of the best experts on this subject based on the ideXlab platform.
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Interferon Regulatory Factor-1 Mediates PPARγ-Induced Apoptosis in Vascular Smooth Muscle Cells
Arteriosclerosis thrombosis and vascular biology, 2003Co-Authors: Yiming Lin, Xiaojun Zhu, Farron L. Mclntee, Hailian Xiao, Jifeng Zhang, Yuqing E. ChenAbstract:Objective— Peroxisome proliferator-activated receptor γ (PPARγ) possesses general beneficial effects on the cardiovascular system, such as inhibition of vascular lesion formation and atherosclerosis. However, molecular mechanisms for these effects are yet to be fully defined. The aim of this study is to elucidate whether Interferon Regulatory Factor-1 (IRF-1), a transcriptional factor with anti-proliferative and pro-apoptotic properties, mediates PPARγ-induced apoptosis in vascular smooth muscle cells (VSMCs). Methods and Results— Using Northern and Western blot analyses, we documented that PPARγ ligands, including ciglitazone, troglitazone, and GW7845, significantly increased IRF-1 expression in VSMCs; however, the PPARα ligand (Wy14643) and PPARδ ligand (GW0742) did not affect its expression. PPARγ-induced IRF-1 expression was abrogated by pretreatment with the PPARγ antagonist GW9662. In contrast, adenoviral expression of PPARγ in VSMCs dramatically increased IRF-1 level. Furthermore, PPARγ activation increased IRF-1 promoter activity but did not affect IRF-1 mRNA stability. Finally, reducing IRF-1 expression by antisense technology attenuated PPARγ-induced VSMC apoptosis through decreasing cyclin-dependent kinase inhibitor p21 cip1 and caspase-3 activity. Conclusion— Our data demonstrate that IRF-1 is a novel PPARγ target gene and mediates PPARγ-induced VSMC apoptosis.