| 1. |
- Ahlqvist, Kristofer, et al.
(författare)
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Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer.
- 2013
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 32:12, s. 1601-1608
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Tidskriftsartikel (refereegranskat)abstract
- B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. As high levels of Bcl-3 expression and activation have been detected in different types of human cancer, Bcl-3 has been labeled a proto-oncogene. Our study uncovered a markedly upregulated Bcl-3 expression in human prostate cancer (PCa), where inflammatory cell infiltration was observed. Elevated Bcl-3 expression in PCa was dependent on the proinflammatory cytokine interleukin-6-mediated STAT3 activation. Microarray analyses, using Bcl-3 knockdown in PCa cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes. Bcl-3 knockdown reduced the abundance of Id-1 and Id-2 proteins and boosted PCa cells to be more receptive to undergoing apoptosis following treatment with anticancer drug. Our data imply that inactivation of Bcl-3 may lead to sensitization of cancer cells to chemotherapeutic drug-induced apoptosis, thus suggesting a potential therapeutic strategy in PCa treatment.Oncogene advance online publication, 14 May 2012; doi:10.1038/onc.2012.175.
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| 2. |
- Ahmed, Neesar, et al.
(författare)
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The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation
- 2011
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 12:12, s. 1-1176
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Tidskriftsartikel (refereegranskat)abstract
- Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Here we demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through 'WW-PPXY' motifs. The Itch-Cyld complex sequentially cleaved Lys63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on the kinase Tak1 to terminate inflammatory signaling via tumor necrosis factor. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyld(-/-) bone marrow-derived macrophages. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells.
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| 3. |
- Bros, Matthias, et al.
(författare)
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Mutated cylindromatosis gene affects the functional state of dendritic cells
- 2010
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 40:10, s. 2848-2857
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Tidskriftsartikel (refereegranskat)abstract
- Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-kappa B signaling pathway and attenuates NF-kappa B and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLDex7/8), display a higher content of nuclear RelB and express elevated levels of NF-kappa B family members as well as of known NF-kappa B-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLDex7/8 DC exhibited a significantly higher primary allogenic T-cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated CYLDex7/8 DC with relB-specific shRNA reduced their T-cell stimulatory capacity. Treatment with the synthetic glucocorticoid dexamethasone known to inhibit NF-kappa B and AP-1 activity reverted the pro-immunogenic phenotype and function of CYLDex7/8 DC and re-established their tolerogenic function. DC derived from CYLD knockout mice showed no functional alterations compared with WT DC. Therefore, although complete loss of CYLD may be compensated for by other endogenous NF-kappa B inhibitors, CYLDex7/8 acts in a dominant negative manner. Our findings raise the question of whether genetic defects associated with increased NF-kappa B activity may result in disturbed maintenance of peripheral tolerance.
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| 4. |
- Chu, Yuanyuan, et al.
(författare)
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A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation
- 2012
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 189:9, s. 4437-4443
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-editing enzyme A20 (TNFAIP3) and the deubiquitinase CYLD are central negative regulators of NF-kappa B signaling. Both can act by removing nonproteolytic K63-linked polyubiquitin chains from an overlapping set of signaling molecules. In B cells, A20 deficiency results in hyperactivity, loss of immune homeostasis, inflammation, and autoimmunity. The reported consequences of CYLD deficiency are controversial, ranging from an absence of effects to dramatic B cell hyperplasia. These differences could be due to varying compensation for the loss of CYLD function by A20. Therefore, to explore potential overlapping physiological functions between A20 and CYLD, we generated and characterized A20/CYLD double-deficient B cells. Interestingly, the lack of both A20 and CYLD did not exacerbate the developmental defects and hyperresponsive activity of A20-deficient B cells. In addition, the extent of B cell activation after in vitro stimulation with anti-CD40, LPS, and CpG was comparable in B cells lacking A20/CYLD and A20 alone. However, in response to BCR cross-linking, we observed small but reproducible additive effects of the lack of A20 and CYLD. Taken together, our results demonstrate that A20 and CYLD do not share significant functions during B cell development and activation. The Journal of Immunology, 2012, 189: 4437-4443.
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| 5. |
- Hallgren, Gina, et al.
(författare)
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Association of nuclear-localized nemo-like kinase with heat-shock protein 27 inhibits apoptosis in human breast cancer cells.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- Nemo-like kinase (NLK), a proline-directed serine/threonine kinase regulated by phosphorylation, can be localized in the cytosol or in the nucleus. Whether the localization of NLK can affect cell survival or cell apoptosis is yet to be disclosed. In the present study we found that NLK was mainly localized in the nuclei of breast cancer cells, in contrast to a cytosolic localization in non-cancerous breast epithelial cells. The nuclear localization of NLK was mediated through direct interaction with Heat shock protein 27 (HSP27) which further protected cancer cells from apoptosis. The present study provides evidence of a novel mechanism by which HSP27 recognizes NLK in the breast cancer cells and prevents NLK-mediated cell apoptosis.
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| 6. |
- Kuphal, S., et al.
(författare)
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GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma
- 2011
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 30:44, s. 4523-4530
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Tidskriftsartikel (refereegranskat)abstract
- CYLD is a deubiquitination enzyme that regulates different cellular processes, such as cell proliferation and cell survival. Mutation and loss of heterozygosity of the CYLD gene causes development of cylindromatosis, a benign tumour originating from the skin. Our study shows that CYLD expression is dramatically downregulated in basal cell carcinoma (BCC), the most common cancer in humans. Reduced CYLD expression in basal cell carcinoma was mediated by GLI1-dependent activation of the transcriptional repressor Snail. Inhibition of GLI1 restored the CYLD expression-mediated Snail signaling pathway, and caused a significant delay in the G1 to S phase transition, as well as proliferation. Our data suggest that GLI1-mediated suppression of CYLD has a significant role in basal cell carcinoma progression. Oncogene (2011) 30, 4523-4530; doi: 10.1038/onc.2011.163; published online 16 May 2011
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| 7. |
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| 8. |
- Liang, Gang, et al.
(författare)
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Serum Response Factor Controls CYLD Expression via MAPK Signaling Pathway.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- Tumor suppressor gene CYLD is a deubiquitinating enzyme which negatively regulates various signaling pathways by removing the lysine 63-linked polyubiquitin chains from several specific substrates. Loss of CYLD in different types of tumors leads to either cell survival or proliferation. In this study we demonstrate that lack of CYLD expression in CYLD-/- MEFs increases proliferation rate of these cells compared to CYLD+/+ in a serum concentration dependent manner without affecting cell survival. The reduced proliferation rate in CYLD+/+ in the presence of serum was due to the binding of serum response factor (SRF) to the serum response element identified in the CYLD promoter for the up-regulation of CYLD levels. The serum regulated recruitment of SRF to the CYLD promoter was dependent on p38 mitogen-activated protein kinase (MAPK) activity. Elimination of SRF by siRNA or inhibition of p38 MAPK reduced the expression level of CYLD and increased cell proliferation. These results show that SRF acts as a positive regulator of CYLD expression, which in turn reduces the mitogenic activation of serum for aberrant proliferation of MEF cells.
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| 9. |
- Masoumi, Katarzyna, et al.
(författare)
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Tumor Suppressor Function of CYLD in Nonmelanoma Skin Cancer.
- 2011
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Ingår i: Journal of Skin Cancer. - : Hindawi Limited. - 2090-2905 .- 2090-2913. ; 2011
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Tidskriftsartikel (refereegranskat)abstract
- Ubiquitin and ubiquitin-related proteins posttranslationally modify substrates, and thereby alter the functions of their targets. The ubiquitination process is involved in various physiological responses, and dysregulation of components of the ubiquitin system has been linked to many diseases including skin cancer. The ubiquitin pathways activated among skin cancers are highly diverse and may reflect the various characteristics of the cancer type. Basal cell carcinoma and squamous cell carcinoma, the most common types of human skin cancer, are instances where the involvement of the deubiquitination enzyme CYLD has been recently highlighted. In basal cell carcinoma, the tumor suppressor protein CYLD is repressed at the transcriptional levels through hedgehog signaling pathway. Downregulation of CYLD in basal cell carcinoma was also shown to interfere with TrkC expression and signaling, thereby promoting cancer progression. By contrast, the level of CYLD is unchanged in squamous cell carcinoma, instead, catalytic inactivation of CYLD in the skin has been linked to the development of squamous cell carcinoma. This paper will focus on the current knowledge that links CYLD to nonmelanoma skin cancers and will explore recent insights regarding CYLD regulation of NF-κB and hedgehog signaling during the development and progression of these types of human tumors.
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| 10. |
- Massoumi, Ramin
(författare)
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CYLD: a deubiquitination enzyme with multiple roles in cancer.
- 2011
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Ingår i: Future Oncology. - : Future Medicine Ltd. - 1479-6694 .- 1744-8301. ; 7:2, s. 285-297
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Tidskriftsartikel (refereegranskat)abstract
- The post-translational modification of different proteins via direct ubiquitin attachment is important for various cellular processes. Dysregulation of components of the ubiqutin system have been linked to many diseases including cancer. CYLD is a deubiquitination enzyme that can cleave the lysine 63-linked polyubiquitin chains from target proteins and regulate cell survival or cell proliferation. Since loss of CYLD expression can be observed in different types of human cancer, it is now well established that CYLD acts as a tumor suppressor gene. Besides its loss of function in human tumors by gene deletion or mutation, CYLD expression can be downregulated at the RNA level if necessary through transcriptional regulation or at the protein level through post-translational modifications. This article summarizes recent advances that link CYLD to different types of human cancer. Identification of CYLD-mediated signaling pathways during the progression of cancer will provide a solid foundation for diagnosis and lead to the development of novel tools for cancer therapy.
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