Nucleoredoxin Negatively Regulates Toll-like Receptor 4 Signaling via Recruitment of Flightless-I to Myeloid Differentiation Primary Response Gene (88)

Hayashi, Tatsuya; Funato, Yosuke; Terabayashi, Takeshi; Morinaka, Akifumi; Sakamoto, Reiko; Ichise, Hirotake; Fukuda, Hiroyuki; Yoshida, Nobuaki; Miki, Hiroaki

doi:10.1074/jbc.m110.106468

Cited by 34 publications

(38 citation statements)

References 31 publications

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“…Oxidation of the WCPPC motif in Nrx leads to dissociation from Dvl and, in consequence, to activation of the transcription factor b-catenin. In TLR4-dependent signaling Nrx was found to be bound to the adaptor protein Fli-1 (for flightless in Drosophila), and control experiments with truncated mutants revealed that the WCPPC motif is essential for binding to Fli-1 (171). Moreover, LPS-triggered TLR4 stimulation and NF-jB activation was substantially enhanced in cells from Nrx -/ -mice, which corroborates the functional relevance of Nrx/Fli-1 interaction (Fig.…”

Section: Brigelius-flohé and Flohésupporting

confidence: 59%

“…However, also inactive Cys to Ser mutants of Nrx did bind to Fli-1, which implies that the active site of the redoxins is not likely involved in their interaction with Fli-1, but leaves open that redox-state-dependent structural changes affect protein/protein interaction. Alternative mechanisms, though, cannot be ruled out, since Nrx also interacts with other proteins such as, for example, HDAC6, Dvl1-3 (171), and the PP2A (137). The routes leading to oxidation and reduction of Nrx remain to be worked out.…”

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

“…Fli-1 inhibits TLR signaling through binding to MyD88 (507) and sequestering the adaptor in the cytosol. This sequestration of MyD88 has now been shown to require Nrx forming a ternary complex of Fli-1, MyD88, and Nrx (171).…”

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

“…Most recently, also Nrx has been demonstrated to be a specific negative regulator of LPS-induced TLR4-mediated signaling (171). Nrx, like tryparedoxin (see section II.D.1), belongs to the redoxin subfamily that is characterized by a WCPPC motif.…”

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

“…It is tempting to speculate that Nrx, like in the Wnt/b-catenin pathway, is released by oxidation, thus allowing TLR signaling to proceed. Interestingly, two more sequence-related proteins were shown to similarly bind to Fli-1: the rod-derived cone viability factor (RdCVF), expressed by photoreceptors and the chromosome 9 open reading frame 121 (C9orf121) protein (171). The former has the active site motif ACPQC, which can be rated as potentially active in disulfide reduction, in the latter the homologous sequence is RCAPS, which is incompatible with disulfide reductase activity but nevertheless could lead to the formation of mixed disulfides.…”

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

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Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Brigelius‐Flohé

Flohé

2011

Antioxidants & Redox Signaling

522

442

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Convincing concepts of redox control of gene transcription have been worked out for prokaryotes and lower eukaryotes, whereas the knowledge on complex mammalian systems still resembles a patchwork of poorly connected findings. The article, therefore, reviews principles of redox regulation with special emphasis on chemical feasibility, kinetic requirements, specificity, and physiological context, taking well investigated mammalian transcription factor systems, nuclear transcription factor of bone marrow-derived lymphocytes (NFjB), and kelch-like ECH-associated protein-1 (Keap1)/Nrf2, as paradigms. Major conclusions are that (i) direct signaling by free radicals is restricted to O 2 -and NO and can be excluded for fast reacting radicals such as OH, OR, or Cl ; (ii) oxidant signals are H 2 O 2 , enzymatically generated lipid hydroperoxides, and peroxynitrite; (iii) free radical damage is sensed via generation of Michael acceptors; (iv) protein thiol oxidation/alkylation is the prominent mechanism to modulate function; (v) redox sensors must be thiol peroxidases by themselves or proteins with similarly reactive cysteine or selenocysteine (Sec) residues to kinetically compete with glutathione peroxidase (GPx)-and peroxiredoxin (Prx)-type peroxidases or glutathione-S-transferases, respectively, a postulate that still has to be verified for putative mammalian sensors. S-transferases and Prxs are considered for system complementation. The impact of NF-jB and Nrf2 on hormesis, management of inflammatory diseases, and cancer prevention is critically discussed. Antioxid. Redox Signal. 15, 2335-2381.

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Section: Brigelius-flohé and Flohésupporting

confidence: 59%

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

See 3 more Smart Citations

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Brigelius‐Flohé

Flohé

2011

Antioxidants & Redox Signaling

522

442

View full text Add to dashboard Cite

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Attenuation of flightless I improves wound healing and enhances angiogenesis in a murine model of type 1 diabetes

et al. 2013

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Aims/hypothesis Skin lesions and ulcerations are severe complications of diabetes that often result in leg amputations. In this study we investigated the function of the cytoskeletal protein flightless I (FLII) in diabetic wound healing. We hypothesised that overexpression of FLII would have a negative effect on diabetic wound closure and modulation of this protein using specific FLII-neutralising antibodies (FnAb) would enhance cellular proliferation, migration and angiogenesis within the diabetic wound.Methods Using a streptozotocin-induced model of diabetes we investigated the effect of altered FLII levels through Flii genetic knockdown, overexpression or treatment with FnAb on wound healing. Diabetic wounds were assessed using histology, immunohistochemistry and biochemical analysis. In vitro and in vivo assays of angiogenesis were used to assess the angiogenic response. Results FLII levels were elevated in the wounds of both diabetic mice and humans. Reduction in the level of FLII improved healing of murine diabetic wounds and promoted a robust pro-angiogenic response with significantly elevated von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)-positive endothelial cell infiltration. Diabetic mouse wounds treated intradermally with FnAb showed improved healing and a significantly increased rate of reepithelialisation. FnAb improved the angiogenic response through enhanced formation of capillary tubes and functional neovasculature. Reducing the level of FLII led to increased numbers of mature blood vessels, increased recruitment of smooth muscle actin-α-positive cells and improved tight junction formation. Conclusions/interpretation Reducing the level of FLII in a wound may be a potential therapeutic approach for the treatment of diabetic foot ulcers.

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Proteomic analysis of the effect of retinoic acids on the human breast cancer cell line MCF-7

et al. 2014

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Breast cancer is the most common type of cancer in women in many areas and is increasing found in developing countries, where the majority of cases are diagnosed in late stages. Retinoic acids, through their associated nuclear receptors, exert intoxicating effects on cell growth, differentiation and apoptosis, and hold significant promise in relation to cancer therapy and chemoprevention. To enhance our understanding of the molecular mechanisms associated with retinoic acids in the breast cancer cell line MCF-7 in a time-dependent manner, we conducted a proteomic analysis of MCF-7 cells using the 2-DE couple with high-throughput mass spectrometry and bioinformatics tools. In the 2-DE patterns of MCF-7 cells treated with retinoic acid in a time-dependent manner, 35 protein spots were found to be differentially expressed. These were 17 increased, 4 decreased, and 14 unevenly expressed protein spots, all of which were analyzed using LTQ-FTICR mass spectrometry. Furthermore, five candidate proteins, up-regulated, were validated by western blotting. These were nucleoredoxin, latexin, aminomethyltransferase, translationally controlled one tumor protein, and rab GDP dissociation inhibitor β. These observations represent novel findings leading to new insight into the exact mechanism behind the effect of retinoic acids in MCF-7 cells while also identifying possible therapeutic targets for breast cancer diagnosis and novel drug development paths for the treatment of this disease.

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Nucleoredoxin Negatively Regulates Toll-like Receptor 4 Signaling via Recruitment of Flightless-I to Myeloid Differentiation Primary Response Gene (88)

Cited by 34 publications

References 31 publications

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Attenuation of flightless I improves wound healing and enhances angiogenesis in a murine model of type 1 diabetes

Proteomic analysis of the effect of retinoic acids on the human breast cancer cell line MCF-7

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