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      An Atlas of Altered Expression of Deubiquitinating Enzymes in Human Cancer

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          Abstract

          Background

          Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin (Ub) or ubiquitin-like gene products, remodel polyubiquitin(-like) chains on target proteins, and counteract protein ubiquitination exerted by E3 ubiquitin-ligases. A wealth of studies has established the relevance of DUBs to the control of physiological processes whose subversion is known to cause cellular transformation, including cell cycle progression, DNA repair, endocytosis and signal transduction. Altered expression of DUBs might, therefore, subvert both the proteolytic and signaling functions of the Ub system.

          Methodology/Principal Findings

          In this study, we report the first comprehensive screening of DUB dysregulation in human cancers by in situ hybridization on tissue microarrays (ISH-TMA). ISH-TMA has proven to be a reliable methodology to conduct this kind of study, particularly because it allows the precise identification of the cellular origin of the signals. Thus, signals associated with the tumor component can be distinguished from those associated with the tumor microenvironment. Specimens derived from various normal and malignant tumor tissues were analyzed, and the “normal” samples were derived, whenever possible, from the same patients from whom tumors were obtained. Of the ∼90 DUBs encoded by the human genome, 33 were found to be expressed in at least one of the analyzed tissues, of which 22 were altered in cancers. Selected DUBs were subjected to further validation, by analyzing their expression in large cohorts of tumor samples. This analysis unveiled significant correlations between DUB expression and relevant clinical and pathological parameters, which were in some cases indicative of aggressive disease.

          Conclusions/Significance

          The results presented here demonstrate that DUB dysregulation is a frequent event in cancer, and have implications for therapeutic approaches based on DUB inhibition.

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          Most cited references67

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          Tissue microarrays for high-throughput molecular profiling of tumor specimens.

          Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.
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            Pfam: clans, web tools and services

            Pfam is a database of protein families that currently contains 7973 entries (release 18.0). A recent development in Pfam has enabled the grouping of related families into clans. Pfam clans are described in detail, together with the new associated web pages. Improvements to the range of Pfam web tools and the first set of Pfam web services that allow programmatic access to the database and associated tools are also presented. Pfam is available on the web in the UK (), the USA (), France () and Sweden ().
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              A genomic and functional inventory of deubiquitinating enzymes.

              Posttranslational modification of proteins by the small molecule ubiquitin is a key regulatory event, and the enzymes catalyzing these modifications have been the focus of many studies. Deubiquitinating enzymes, which mediate the removal and processing of ubiquitin, may be functionally as important but are less well understood. Here, we present an inventory of the deubiquitinating enzymes encoded in the human genome. In addition, we review the literature concerning these enzymes, with particular emphasis on their function, specificity, and the regulation of their activity.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                25 January 2011
                : 6
                : 1
                : e15891
                Affiliations
                [1 ]IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
                [2 ]Istituto Europeo di Oncologia, Milan, Italy
                [3 ]Dipartimento di Medicina, Chirurgia e Odontoiatria, Università degli Studi di Milano, Milan, Italy
                Karolinska Institutet, Sweden
                Author notes

                Conceived and designed the experiments: PPDF SC. Performed the experiments: CL MC MD. Analyzed the data: PN GM MD. Contributed reagents/materials/analysis tools: GV MGJ. Wrote the paper: CL SC PPDF.

                Article
                PONE-D-10-02850
                10.1371/journal.pone.0015891
                3026797
                21283576
                bfc47a85-b396-4db8-a2fb-006f04813985
                Luise et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 2 October 2010
                : 29 November 2010
                Page count
                Pages: 10
                Categories
                Research Article
                Biology
                Genetics
                Molecular Genetics
                Gene Regulation
                Genetic Screens
                Medicine
                Diagnostic Medicine
                Pathology
                Anatomical Pathology

                Uncategorized
                Uncategorized

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