CYLD: A Multifunctional Deubiquitinase

Glittenberg, Marcus; Ligoxygakis, Petros

doi:10.4161/fly.5399

Cited by 16 publications

(13 citation statements)

References 26 publications

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“…Interestingly, most of the NF-κB targets we have analysed, were all significantly up-regulated in hypoxia, when the Cyld function was impaired (Figure 5B). These results suggest, that Cyld controls NF-κB activation in hypoxia much like it does in response to infection [27] in this model organism.…”

Section: Resultsmentioning

confidence: 88%

“…One study demonstrated that Cyld is targeted for degradation by HPV (human papillomavirus) E6 virus, to prolong NF-κB activation following hypoxia [36]. In Drosophila , Cyld has been previously shown to interact with the IKKγ homologue (Kenny) and restrict NF-κB's activity both in basal and following bacterial infection, via the IMD pathway [27]. Our results are in agreement with this finding, as hypoxia activates mainly the IMD pathway in Drosophila .…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia activates IKK–NF-κB and the immune response in Drosophila melanogaster

et al. 2014

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Hypoxia, or low oxygen availability, is an important physiological and pathological stimulus for multicellular organisms. Molecularly, hypoxia activates a transcriptional programme directed at restoration of oxygen homoeostasis and cellular survival. In mammalian cells, hypoxia not only activates the HIF (hypoxia-inducible factor) family, but also additional transcription factors such as NF-κB (nuclear factor κB). Here we show that hypoxia activates the IKK–NF-κB [IκB (inhibitor of nuclear factor κB)–NF-κB] pathway and the immune response in Drosophila melanogaster. We show that NF-κB activation is required for organism survival in hypoxia. Finally, we identify a role for the tumour suppressor Cyld, as a negative regulator of NF-κB in response to hypoxia in Drosophila. The results indicate that hypoxia activation of the IKK–NF-κB pathway and the immune response is an important and evolutionary conserved response.

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Section: Resultsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Hypoxia activates IKK–NF-κB and the immune response in Drosophila melanogaster

et al. 2014

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“…CYLD was first described as a tumor suppressor gene that is mutated in patients with familial cylindromatosis, a disease characterized by numerous tumors of hair follicles and sweat glands of the head and neck (16). Recent in vitro studies and the development of CYLD knock-out ( Cyld −/− ) mice have suggested an important role for CYLD in immune function and tumorigenesis (17, 18). CYLD mediates the hydrolysis of lysine 63-linked polyubiquitin chains from TNF receptor-associated factors (TRAFs), TGF-β activated kinase-1 (TAK1), and IKKγ, the regulatory subunit of the IKK complex (14, 19).…”

Section: Introductionmentioning

confidence: 99%

The Deubiquitinase CYLD Targets Smad7 Protein to Regulate Transforming Growth Factor β (TGF-β) Signaling and the Development of Regulatory T Cells

Zhao

Thornton

Kinney

et al. 2011

Journal of Biological Chemistry

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Background: CYLD is a deubiquitinating enzyme (DUB) that hydrolyzes Lys-63-linked polyubiquitin chains that are attached covalently to cellular proteins.Results: CYLD knock-out mice have increased numbers of regulatory T cells (Tregs) in peripheral lymphoid organs but not in the thymus.Conclusion: CYLD regulates lysine 63-linked ubiquitination of Smad7 to control the development of peripheral Tregs.Significance: TGF-β signaling in T cells is regulated by lysine 63-Linked ubiquitination.

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“…In HCC, IKK· and IKKß have been found to be highly expressed, causing enhanced NF-κB activation, and thus contributing to the malignant properties of liver cancer (19). There is much evidence that K-63-linked ubiquitin chains facilitate the protein-protein interactions in the NF-κB signaling cascade (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

“…CYLD encodes a protein containing an ubiquitin C-terminal hydrolase domain, allowing the protein to act as a deubiquitinating enzyme (20). CYLD removes K-63-linked polyubiquitin chains from proteins involved in the NF-κB signaling pathway (21). In vitro studies have identified CYLD as a protein associated with important cellular processes, such as cellular activation, apoptosis, inflammation, proliferation and tumorigenesis (16,22,(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells

Urbanik

Köhler²,

Boger³

et al. 2010

Int J Oncol

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Abstract. The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomaldominant predisposition to multiple tumors of the skin appendages. CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-κB activating proteins. In order to investigate the role of CYLD in apoptotic signaling in human hepatocellular carcinoma (HCC) cells, we first studied the expression levels of CYLD in HCC tissues. CYLD expression was lower in HCC both at protein and mRNA levels compared to the surrounding non-malignant tissue. In order to further study the role of CYLD in the apoptotic sensitivity of HCC cells, CYLD was specifically down-regulated in HCC cell lines via RNA interference. The specific down-regulation of CYLD resulted in increased resistance towards treatment with doxorubicin, 5-fluorouracil and cisplatin. In addition, the downregulation of CYLD in HCC cells decreased the sensitivity towards tumor necrosis factor-·-induced apoptosis. The CYLD knockdown also led to the degradation of the NF-κB inhibitor, IκB-·, resulting in enhanced NF-κB activity in HCC cells. Finally, we found that CYLD expression was triggered by the multikinase inhibitor, sorafenib, by the inhibition of Raf-1, as well as by the blockage of the prosurvival kinases, MEK (U0126) and the epidermal growth factor receptor (AG1478). In summary, we show that CYLD is down-regulated in human HCC and is involved in the apoptotic resistance of HCC cells. Our data indentify the reconstitution of CYLD expression as an attractive approach for overcoming resistance to treatment in HCC.

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CYLD: A Multifunctional Deubiquitinase

Cited by 16 publications

References 26 publications

Hypoxia activates IKK–NF-κB and the immune response in Drosophila melanogaster

Hypoxia activates IKK–NF-κB and the immune response in Drosophila melanogaster

The Deubiquitinase CYLD Targets Smad7 Protein to Regulate Transforming Growth Factor β (TGF-β) Signaling and the Development of Regulatory T Cells

Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells

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