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      The BTB-zinc Finger Transcription Factor Abrupt Acts as an Epithelial Oncogene in Drosophila melanogaster through Maintaining a Progenitor-like Cell State

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          Abstract

          The capacity of tumour cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila melanogaster, we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled ( scrib), and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumours in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (a homologue of SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumour formation in cooperation with the loss of Scrib. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scrib promotes cooperation with Abrupt through impaired Hippo signalling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK (Jun kinase) signalling, which is required for tumour cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, identify mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumours in Drosophila can be characterised by the maintenance of a progenitor-like state.

          Author Summary

          Cancer is a multigenic process, involving cooperative interactions between oncogenes or tumour suppressors. In this study, in a genetic screen in the vinegar fly, Drosophila melanogaster, for genes that cooperate with a mutation in the cell polarity (shape) regulator, scribbled (scrib), we identify a novel cooperative oncogene, abrupt. Expression of abrupt in scrib mutant tissue in the developing eye/antennal epithelium results in overgrown invasive tumours. abrupt encodes a BTB-zinc finger transcription factor, which has homology to several cancer-causing proteins in humans, such as BCL6. Analysis of the Abrupt targets and misexpressed genes in abrupt expressing-tissue and abrupt-expressing scrib mutant tumours, revealed cell fate regulators as a major class of targets. Thus, our results reveal that deregulation of multiple cell fate factors by Abrupt expression in the context of polarity disruption is associated with a progenitor-like cell state and the formation of overgrown invasive tumours. Our findings suggest that defective polarity may also be a critical factor in BTB-zinc finger-driven human cancers, and warrants further investigation into this issue.

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          The UCSC Genome Browser database: update 2011

          The University of California, Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online access to a database of genomic sequence and annotation data for a wide variety of organisms. The Browser also has many tools for visualizing, comparing and analyzing both publicly available and user-generated genomic data sets, aligning sequences and uploading user data. Among the features released this year are a gene search tool and annotation track drag-reorder functionality as well as support for BAM and BigWig/BigBed file formats. New display enhancements include overlay of multiple wiggle tracks through use of transparent coloring, options for displaying transformed wiggle data, a ‘mean+whiskers’ windowing function for display of wiggle data at high zoom levels, and more color schemes for microarray data. New data highlights include seven new genome assemblies, a Neandertal genome data portal, phenotype and disease association data, a human RNA editing track, and a zebrafish Conservation track. We also describe updates to existing tracks.
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            NCBI Reference Sequences: current status, policy and new initiatives

            NCBI's Reference Sequence (RefSeq) database (http://www.ncbi.nlm.nih.gov/RefSeq/) is a curated non-redundant collection of sequences representing genomes, transcripts and proteins. RefSeq records integrate information from multiple sources and represent a current description of the sequence, the gene and sequence features. The database includes over 5300 organisms spanning prokaryotes, eukaryotes and viruses, with records for more than 5.5 × 106 proteins (RefSeq release 30). Feature annotation is applied by a combination of curation, collaboration, propagation from other sources and computation. We report here on the recent growth of the database, recent changes to feature annotations and record types for eukaryotic (primarily vertebrate) species and policies regarding species inclusion and genome annotation. In addition, we introduce RefSeqGene, a new initiative to support reporting variation data on a stable genomic coordinate system.
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              Module map of stem cell genes guides creation of epithelial cancer stem cells.

              Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                July 2013
                July 2013
                18 July 2013
                : 9
                : 7
                : e1003627
                Affiliations
                [1 ]Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
                [2 ]Department of Anatomy and Cell Biology, The University of Melbourne, Melbourne, Victoria, Australia
                [3 ]Departament de Genètica i Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain
                [4 ]Instituto de Biología Molecular de Barcelona (CSIC), Parc Cientific de Barcelona, Barcelona, Spain
                [5 ]Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
                [6 ]Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan
                [7 ]Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
                [8 ]Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia
                [9 ]Department of Genetics, The University of Melbourne, Melbourne, Victoria, Australia
                University of Washington, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AMB HER. Performed the experiments: NT VKS JEB KRG KD AMB. Analyzed the data: NT VKS JEB KRG KD LFW EB EMB MC JE HER AMB. Contributed reagents/materials/analysis tools: EB EMB MC JE TA. Wrote the paper: AMB. Prepared Figures: NT LFW AMB. Editorial guidance: EMB HER.

                ¶ Co-senior authors.

                Article
                PGENETICS-D-13-00022
                10.1371/journal.pgen.1003627
                3715428
                23874226
                2de03eef-3a57-4a39-ab75-849977951bd6
                Copyright @ 2013

                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 January 2013
                : 30 May 2013
                Page count
                Pages: 24
                Funding
                This work was supported by grants from the Australian National Health and Medical Research Council (NHMRC) to AMB (NHMRC Grants #350396 and #509051) and HER (NHMRC Senior research Fellowship B and NHMRC Grants #400211 and #628401), NIH grant (1R21CA098997-01) to HER, Peter MacCallum Cancer Center Internal Grant to HER, a Development Travel Award to NT, and a Spanish Ministry of Education and Science grant to MC (CSD2007-00008) to support the Bioinformatics Platform. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Medicine

                Genetics
                Genetics

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