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      Upregulation of Nuclear Factor-Related Kappa B Suggests a Disorder of Transcriptional Regulation in Minimal Change Nephrotic Syndrome

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          Abstract

          Immune mechanisms underlying the pathophysiology of idiopathic nephrotic syndrome, the most frequent glomerular disease in children, are believed to involve a systemic disorder of T cell function and cell mediated immunity. How these perturbations take place remains unclear. We report here that NFRKB, a member of the chromatin remodeling complex, is upregulated in MCNS relapse, mainly in CD4+T cells and B cells and undergo post-translational modifications including sumoylation. We showed that NFRKB was highly expressed in nuclear compartment during the relapse, while it was restricted to cytoplasm in remission. NFRKB induced the activation of AP1 signaling pathway by upregulating the expression of c-jun. We showed that NFRKB promotes hypomethylation of genomic DNA, suggesting its implication in regulation of gene expression by enhancing the binding of transcription factors through chromatin remodeling. These results suggest for the first time that NFRKB may be involved in the disorders of transcriptional regulation commonly observed in MCNS relapse.

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          Most cited references29

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          AP-1 function and regulation.

          AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. As the complexity of our knowledge of AP-1 factors has increased, our understanding of their physiological function has decreased. This trend, however, is beginning to be reversed due to the recent studies of gene-knockout mice and cell lines deficient in specific AP-1 components. Such studies suggest that different AP-1 factors may regulate different target genes and thus execute distinct biological functions. Also, the involvement of AP-1 factors in functions such as cell proliferation and survival has been made somewhat clearer as a result of such studies. In addition, there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP-1 activity. In addition to regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators.
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            Pathogenesis of lipoid nephrosis: a disorder of T-cell function.

            J Shalhoub (1974)
            Clinical observations suggest that lipoid nephrosis is produced by a systemic abnormality of T-cell function resulting in the secretion of a circulating chemical mediator toxic to an immunologically innocent glomerular basement membrane. The lack of evidence of a humoral antibody response, remission induced by measles which modifies cell-mediated immunity, the therapeutic benefits of steroids and cyclophosphamide which also abate cell-mediated responses, and the occurrence of this syndrome in Hodgkin's disease support this hypothesis. The susceptibility of untreated patients to pneumococcal infections may be of primary or secondary pathogenetic importance. Taken together, the data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency disease.
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              Redox regulation of fos and jun DNA-binding activity in vitro.

              The proto-oncogenes c-fos and c-jun function cooperatively as inducible transcription factors in signal transduction processes. Their protein products, Fos and Jun, form a heterodimeric complex that interacts with the DNA regulatory element known as the activator protein-1 (AP-1) binding site. Dimerization occurs via interaction between leucine zipper domains and serves to bring into proper juxtaposition a region in each protein that is rich in basic amino acids and that forms a DNA-binding domain. DNA binding of the Fos-Jun heterodimer was modulated by reduction-oxidation (redox) of a single conserved cysteine residue in the DNA-binding domains of the two proteins. Furthermore, a nuclear protein was identified that reduced Fos and Jun and stimulated DNA-binding activity in vitro. These results suggest that transcriptional activity mediated by AP-1 binding factors may be regulated by a redox mechanism.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                23 January 2012
                : 7
                : 1
                : e30523
                Affiliations
                [1 ]INSERM U 955, Créteil, France
                [2 ]Université Paris-Est, Créteil, France
                [3 ]AP-HP, Groupe Hospitalier Henri Mondor-Albert Chenevier, Service de Néphrologie, Créteil, France
                [4 ]Institut Francilien de Recherche en Néphrologie et Transplantation, Henri Mondor Hospital, Creteil, France
                Cardiovascular Research Institute Maastricht - Maastricht University, The Netherlands
                Author notes

                Conceived and designed the experiments: AP VA DS. Performed the experiments: AP VA MC. Analyzed the data: AP VA PL DS. Contributed reagents/materials/analysis tools: AP VA DS. Wrote the paper: AP VA DS.

                Article
                PONE-D-11-16704
                10.1371/journal.pone.0030523
                3264618
                22291976
                6b24b825-9e5f-4649-a170-b5b66e980da1
                Audard et al. 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 credited.
                History
                : 30 August 2011
                : 18 December 2011
                Page count
                Pages: 9
                Categories
                Research Article
                Biology
                Genetics
                Gene Expression
                Molecular Genetics
                Immunology
                Molecular Cell Biology
                Signal Transduction
                Signaling in Selected Disciplines
                Medicine
                Nephrology

                Uncategorized
                Uncategorized

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