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      The cylindromatosis ( CYLD) gene and head and neck tumorigenesis

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          Abstract

          Germline CYLD mutation is associated with the development of a rare inheritable syndrome, called the CYLD cutaneous syndrome. Patients with this syndrome are distinctly presented with multiple tumors in the head and neck region, which can grow in size and number over time. Some of these benign head and neck tumors can turn into malignancies in some individuals. CYLD has been identified to be the only tumor suppressor gene reported to be associated with this syndrome thus far. Here, we summarize all reported CYLD germline mutations associated with this syndrome, as well as the reported paired somatic CYLD mutations of the developed tumors. Interestingly, whole-exome sequencing (WES) studies of multiple cancer types also revealed CYLD mutations in many human malignancies, including head and neck cancers and several epithelial cancers. Currently, the role of CYLD mutations in head and neck carcinogenesis and other cancers is poorly defined. We hope that this timely review of recent findings on CYLD genetics and animal models for oncogenesis can provide important insights into the mechanism of head and neck tumorigenesis.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s41199-016-0012-y) contains supplementary material, which is available to authorized users.

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          Most cited references 110

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

           J. Gao,  B. Aksoy,  U Dogrusoz (2013)
          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            The ubiquitin system for protein degradation.

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              Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling.

              Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes. The CYLD gene encodes a deubiquitinase that removes lysine 63-linked ubiquitin chains from TRAF2 and inhibits p65/p50 NF-kappaB activation. Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels. The cyclin D1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of Bcl-3-associated NF-kappaB p50 and p52. In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld binds and deubiquitinates Bcl-3, thereby preventing nuclear accumulation of Bcl-3 and p50/Bcl-3- or p52/Bcl-3-dependent proliferation. These data indicate that, depending on the external signals, Cyld can negatively regulate different NF-kappaB pathways; inactivation of TRAF2 controls survival and inflammation, while inhibition of Bcl-3 controls proliferation and tumor growth.
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                Author and article information

                Contributors
                (852)-3943-5388 , vlui002@cuhk.edu.hk
                Journal
                Cancers Head Neck
                Cancers Head Neck
                Cancers of the Head & Neck
                BioMed Central (London )
                2059-7347
                8 September 2016
                8 September 2016
                2016
                : 1
                Affiliations
                [1 ]GRID grid.194645.b, ISNI 0000000121742757, Department of Clinical Oncology, Li-Ka Shing Faculty of Medicine, , the University of Hong Kong, ; Hongkong, SAR Hong Kong
                [2 ]GRID grid.194645.b, ISNI 0000000121742757, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, , the University of Hong Kong, ; Hongkong, SAR Hong Kong
                [3 ]GRID grid.10784.3a, ISNI 0000000419370482, School of Biomedical Sciences, Faculty of Medicine, , the Chinese University of Hong Kong, ; Hongkong, SAR Hong Kong
                Article
                12
                10.1186/s41199-016-0012-y
                6460526
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002920, Research Grants Council, University Grants Committee;
                Award ID: PF14-17557
                Award ID: 17114874
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003802, University Research Committee, University of Hong Kong;
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                © The Author(s) 2016

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