Direct Inhibition of TNF-α Promoter Activity by Fanconi Anemia Protein FANCD2

Matsushita, Nobuko; Endo, Yoshihisa; Sato, Koichi; Kurumizaka, Hitoshi; Yamashita, Takayuki; Takata, Minoru; Yanagi, Shigeru

doi:10.1371/journal.pone.0023324

Cited by 29 publications

(24 citation statements)

References 42 publications

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“…In addition, we observed that GSK3β inhibition triggered activation of the FA pathway as measured by formation of the long form of FANCD2. Recent studies support a role of the FA core complex via FANCD2 in transcription, both activation and repression (25)(26)(27). Taken together, those studies and our results imply that FA core complex activity may modulate β-catenin function.…”

Section: Discussionsupporting

confidence: 88%

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Huard

Tremblay

Magron

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with a progressive decline in hematopoietic stem cells, developmental defects, and predisposition to cancer. These various phenotypic features imply a role of FA proteins in molecular events regulating cellular homeostasis. Interestingly, we previously found that the Fanconi C protein (FANCC) interacts with the C-terminalbinding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with β-catenin, and that β-catenin activation through glycogen synthase kinase 3β inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. β-catenin and FANCC nuclear entry is defective in FA mutant cells and in cells depleted of the Fanconi A protein or FANCD2, suggesting that integrity of the FA pathway is required for FANCC nuclear activity. We also report that FANCC with CtBP1 acts as a negative regulator of Dickkopf-1 (DKK1) expression, and that a FA disease-causing mutation in FANCC abrogates this function. Our findings reveal that a defective FA pathway leads to up-regulation of DKK1, a molecule involved in hematopoietic malignancies.

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Section: Discussionsupporting

confidence: 88%

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Huard

Tremblay

Magron

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…To address whether H3K4me2, which is associated with increased gene expression, is enriched at the TNF promoter in an NF-κB binding region, ChIP-qPCR was applied [24]. When compared to total input DNA, there was a significant enrichment of H3K4me2 at the TNF promoter at the kB1 region, an enrichment that was inhibited by pre-incubation with HCQ (11.2 ± 1.2% vs 6.6 ± 0.7%, N = 3, p = 0.03, hY3 vs hY3 + HCQ, respectively, Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting downstream transcription factors and epigenetic modifications following Toll-like receptor 7/8 ligation to forestall tissue injury in anti-Ro60 associated heart block

Clancy

Markham

Reed

et al. 2016

Journal of Autoimmunity

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Based on the consistent demonstration of fibrosis of the atrioventricular node surrounded by macrophages and multinucleated giant cells in anti-Ro antibody exposed fetuses dying with heart block, this study focuses on macrophage signaling stimulated by ssRNA associated with the Ro60 protein and the impact of antagonizing innate cell drivers such as TLR7/8. Transcriptome and epigenetic modifications which affect transcription factors, NF-κB and STAT1, were selected to evaluate the phenotype of macrophages in which TLR7/8 was ligated following treatment with either anti-Ro60/Ro60/hY3 RNA immune complexes or transfection with hY3. Based on microarray, TNF and IL6 were among the most highly upregulated genes in both stimulated conditions, each of which was significantly inhibited by preincubation with hydroxychloroquine (HCQ). In contrast, following stimulation of macrophages with either TNF-α or IFN-α, which do not signal through TLR, the resultant gene expression was refractory to HCQ. Ligation of TLR7/8 resulted in increased histone methylation as measured by increased H3K4me2, a requirement for binding of NF-κB at certain promoters, specifically the kB1 region in the TNF promoter (ChIP-qPCR), which was significantly decreased by HCQ. In summary, these results support that the HCQ-sensitive phenotype of hY3 stimulated macrophages reflects the bifurcation of TLR downstream signals involving NF-κB and STAT 1 pathways and for the former dimethylation of H3K4. Accordingly, HCQ may act more as a preventive measure in downregulating the initial production of IFN-α or TNF-α and not affect the resultant autocoid stimulation reflected in TNF-α and IFN-α responsive genes. The beneficial scope of antimalarials in the prevention of organ damage, inclusive of heart block in an anti-Ro offspring or more broadly SLE, may include in part, a mechanism targeting TLR-dependent epigenetic modification.

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“…We show that FANCD2, a critical downstream component of the FA pathway, binds to the promoter region of SMAD1. Activated FANCD2 has been previously reported to decrease transcription of the TNFα gene and to increase transcription of the TAp63 gene (Matsushita et al, 2011; Park et al, 2013). Our results indicate that hyperactive TGF-β pathway in FA cells contributes to the impairment of DNA repair due to downregulation of HR activity.…”

Section: Discussionmentioning

confidence: 99%

TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia

et al. 2016

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SUMMARY Fanconi Anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-β (TGF-β) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-β pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived from FA mice and FA patients. Inhibition of TGF-β signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-β signaling contributes to the BMF in FA by impairing HSPC function, and may be a potential therapeutic target for the treatment of FA.

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Direct Inhibition of TNF-α Promoter Activity by Fanconi Anemia Protein FANCD2

Cited by 29 publications

References 42 publications

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Targeting downstream transcription factors and epigenetic modifications following Toll-like receptor 7/8 ligation to forestall tissue injury in anti-Ro60 associated heart block

TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia

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