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Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5

BACKGROUND: Interferon regulatory factor (IRF) family members have been implicated as critical transcription factors that function in immune response, hematopoietic differentiation and cell growth regulation. Activation of IRF-5 results in the production of pro-inflammatory cytokines such as TNFα, I...

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Autores principales: Yang, Long, Zhao, Tiejun, Shi, Xiaoliu, Nakhaei, Peyman, Wang, Yunling, Sun, Qiang, Hiscott, John, Lin, Rongtuan
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677155/
https://www.ncbi.nlm.nih.gov/pubmed/19430534
http://dx.doi.org/10.1371/journal.pone.0005500
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author Yang, Long
Zhao, Tiejun
Shi, Xiaoliu
Nakhaei, Peyman
Wang, Yunling
Sun, Qiang
Hiscott, John
Lin, Rongtuan
author_facet Yang, Long
Zhao, Tiejun
Shi, Xiaoliu
Nakhaei, Peyman
Wang, Yunling
Sun, Qiang
Hiscott, John
Lin, Rongtuan
author_sort Yang, Long
collection PubMed
description BACKGROUND: Interferon regulatory factor (IRF) family members have been implicated as critical transcription factors that function in immune response, hematopoietic differentiation and cell growth regulation. Activation of IRF-5 results in the production of pro-inflammatory cytokines such as TNFα, IL6 and IL12p40, as well as type I interferons. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we identify a G202C (position relative to translation start codon) missense-mutation transcript of IRF-5 in transformed B and T cell lines, which were either infected or non-infected by viruses, and peripheral blood from ATL or CLL patients. The mutated transcript encodes a novel protein in which the sixty-eighth amino acid, Alanine, is substituted by Proline (IRF-5P68) in the DNA binding domain of IRF-5. IRF-5P68 phenotype results in a complete loss of its DNA-binding activity and functions as a dominant negative molecule through interacting with wild type IRF-5. Co-expression of IRF-5P68 inhibits MyD88-mediated IRF-5 transactivation. Moreover, Toll-like receptor (TLR)-dependent IL6 and IL12P40 production induced by lipopolysaccharide (LPS), R837 or CpG ODN 1826 was reduced in IRF-5 (P68) expressing cells as compared to the control cells. CONCLUSION: IRF-5P68 acts as a dominant negative regulator that interferes with IRF-5-mediated production of pro-inflammatory cytokines. The functional characterization of the novel IRF-5 mutant in transformed B and T cell lines and in ATL and CLL patients may lead to a better understanding of the role of these transcriptional regulators in hematopoietic malignancies.
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spelling pubmed-26771552009-05-11 Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5 Yang, Long Zhao, Tiejun Shi, Xiaoliu Nakhaei, Peyman Wang, Yunling Sun, Qiang Hiscott, John Lin, Rongtuan PLoS One Research Article BACKGROUND: Interferon regulatory factor (IRF) family members have been implicated as critical transcription factors that function in immune response, hematopoietic differentiation and cell growth regulation. Activation of IRF-5 results in the production of pro-inflammatory cytokines such as TNFα, IL6 and IL12p40, as well as type I interferons. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we identify a G202C (position relative to translation start codon) missense-mutation transcript of IRF-5 in transformed B and T cell lines, which were either infected or non-infected by viruses, and peripheral blood from ATL or CLL patients. The mutated transcript encodes a novel protein in which the sixty-eighth amino acid, Alanine, is substituted by Proline (IRF-5P68) in the DNA binding domain of IRF-5. IRF-5P68 phenotype results in a complete loss of its DNA-binding activity and functions as a dominant negative molecule through interacting with wild type IRF-5. Co-expression of IRF-5P68 inhibits MyD88-mediated IRF-5 transactivation. Moreover, Toll-like receptor (TLR)-dependent IL6 and IL12P40 production induced by lipopolysaccharide (LPS), R837 or CpG ODN 1826 was reduced in IRF-5 (P68) expressing cells as compared to the control cells. CONCLUSION: IRF-5P68 acts as a dominant negative regulator that interferes with IRF-5-mediated production of pro-inflammatory cytokines. The functional characterization of the novel IRF-5 mutant in transformed B and T cell lines and in ATL and CLL patients may lead to a better understanding of the role of these transcriptional regulators in hematopoietic malignancies. Public Library of Science 2009-05-11 /pmc/articles/PMC2677155/ /pubmed/19430534 http://dx.doi.org/10.1371/journal.pone.0005500 Text en Yang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Yang, Long
Zhao, Tiejun
Shi, Xiaoliu
Nakhaei, Peyman
Wang, Yunling
Sun, Qiang
Hiscott, John
Lin, Rongtuan
Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5
title Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5
title_full Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5
title_fullStr Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5
title_full_unstemmed Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5
title_short Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5
title_sort functional analysis of a dominant negative mutation of interferon regulatory factor 5
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677155/
https://www.ncbi.nlm.nih.gov/pubmed/19430534
http://dx.doi.org/10.1371/journal.pone.0005500
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