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Alternative Splicing: Role in Cancer Development and Progression International Journal of Cell Biology Alternative Splicing: Role in Cancer Development and Progression Guest Editors: Claudia Ghigna, Michael Ladomery, and Claudio Sette Alternative Splicing: Role in Cancer Development and Progression International Journal of Cell Biology Alternative Splicing: Role in Cancer Development and Progression Guest Editors: Claudia Ghigna, Michael Ladomery, and Claudio Sette Copyright © 2013 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “International Journal of Celllogy.” Bio All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Paul N. Adler, USA Wiljan Hendriks, The Netherlands Liza Pon, USA Emad Alnemri, USA Paul J. Higgins, USA Jerome Rattner, Canada Avri Ben-Ze’ev, Israel Michael Hortsch, USA Maria Roubelakis, Greece Jeannette Chloe Bulinski, USA Pavel Hozak, Czech Republic Afshin Samali, Ireland Michael Bustin, USA Jeremy Hyams, France Michael Peter Sarras, USA John Cooper, USA Anton M. Jetten, USA Hirofumi Sawai, Japan Adrienne D. Cox, USA Edward M. Johnson, USA R. Seger, Israel J. R. Davie, Canada Daniel P. Kiehart, USA Barry D. Shur, USA Govindan Dayanithi, France Sharad Kumar, Australia Arnoud Sonnenberg, The Netherlands Arun M. Dharmarajan, Australia Paul Marks, USA Gary S. Stein, USA Dara Dunican, Ireland Seamus J. Martin, Ireland Tung Tien Sun, USA William Dunn, USA Manuela Martins-Green, USA Ming Tan, USA Victor Faundez, USA Takeshi Noda, Japan Guido Tarone, Italy Roland Foisner, Austria Helga Ogmundsd¨ ottir,´ Iceland Jean-Pierre Tassan, France Hans Hermann Gerdes, Norway Shoichiro Ono, USA Richard Tucker, USA Richard Gomer, USA Howard Beverley Osborne, France Andre Van Wijnen, USA Hinrich Gronemeyer, France Markus Paulmichl, Austria Gerhard Wiche, Austria Mehran Haidari, USA H. Benjamin Peng, Hong Kong Steve Winder, UK Thomas Hays, USA Craig Pikaard, USA Timothy J. Yen, USA Contents Alternative Splicing: Role in Cancer Development and Progression, Claudio Sette, Michael Ladomery, and Claudia Ghigna Volume 2013, Article ID 421606, 2 pages Oncogenic Alternative Splicing Switches: Role in Cancer Progression and Prospects for Therapy, Serena Bonomi, Stefania Gallo, Morena Catillo, Daniela Pignataro, Giuseppe Biamonti, and Claudia Ghigna Volume 2013, Article ID 962038, 17 pages U1 snRNP-Dependent Suppression of Polyadenylation: Physiological Role and Therapeutic Opportunities in Cancer, Lee Spraggon and Luca Cartegni Volume 2013, Article ID 846510, 10 pages Role of Pseudoexons and Pseudointrons in Human Cancer, Maurizio Romano, Emanuele Buratti, and Diana Baralle Volume 2013, Article ID 810572, 16 pages RNA Splicing: A New Player in the DNA Damage Response, Silvia C. Lenzken, Alessia Loffreda, and Silvia M. L. Barabino Volume 2013, Article ID 153634, 12 pages Aberrant Alternative Splicing Is Another Hallmark of Cancer,MichaelLadomery Volume 2013, Article ID 463786, 6 pages Ewing Sarcoma Protein: A Key Player in Human Cancer, Maria Paola Paronetto Volume 2013, Article ID 642853, 12 pages Regulation of the Ras-MAPK and PI3K-mTOR Signalling Pathways by Alternative Splicing in Cancer, Zahava Siegfried, Serena Bonomi, Claudia Ghigna, and Rotem Karni Volume 2013, Article ID 568931, 9 pages Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer, Chiara Naro and Claudio Sette Volume 2013, Article ID 151839, 15 pages Alternative Splicing Regulation of Cancer-Related Pathways in Caenorhabditis elegans:AnInVivo Model System with a Powerful Reverse Genetics Toolbox,SergioBarberan-Soler´ and James Matthew Ragle Volume 2013, Article ID 636050, 10 pages Alternative Splicing Programs in Prostate Cancer,ClaudioSette Volume 2013, Article ID 458727, 10 pages Expression of Tra2 in Cancer Cells as a Potential Contributory Factor to Neoplasia and Metastasis, Andrew Best, Caroline Dagliesh, Ingrid Ehrmann, Mahsa Kheirollahi-Kouhestani, Alison Tyson-Capper, and David J. Elliott Volume 2013, Article ID 843781, 9 pages Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance, Claire Jackson, David Browell, Hannah Gautrey, and Alison Tyson-Capper Volume 2013, Article ID 973584, 8 pages Hindawi Publishing Corporation International Journal of Cell Biology Volume 2013, Article ID 421606, 2 pages http://dx.doi.org/10.1155/2013/421606 Editorial Alternative Splicing: Role in Cancer Development and Progression Claudio Sette,1,2 Michael Ladomery,3 and Claudia Ghigna4 1 Dipartimento di Biomedicina e Prevenzione, Universita` di Roma Tor Vergata, Via Montpellier 1, 00133 Roma, Italy 2 Fondazione Santa Lucia, Laboratorio di Neuroembriologia, Via del Fosso di Fiorano 64, 00143 Roma, Italy 3 Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK 4 Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia, Italy Correspondence should be addressed to Claudia Ghigna; [email protected] Received 22 September 2013; Accepted 22 September 2013 Copyright © 2013 Claudio Sette et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alternative splicing of precursor messenger RNAs (pre- the role of alternative splicing in cancer still remain to be mRNAs) is a fundamental step in the regulation of gene addressed. expression. This processing step of the nascent messenger Themainfocusofthisspecialissueistoemphasizekey amplifies the coding potential of eukaryotic genomes by mechanisms involved in oncogenic splicing changes, their allowing the production of multiple protein isoforms with connection with other steps of gene expression, and the distinct structural and functional properties. The advent therapeutic potential of cancer-associated alternative splicing of high-throughput sequencing techniques has recently isoforms. revealed that alternative splicing of exons and introns repre- More specifically, M. Ladomery discusses alternative sents a major source of proteomic diversity in complex organ- splicing in the context of the so-called hallmarks of cancer, isms characterized by a limited number of protein-coding originally proposed by Hanahan and Weinberg in 2000. genes. Nevertheless, the evolutionary advantage provided by The list of hallmarks was originally six; recently itwas alternative splicing can also turn into a source of deleterious augmented to ten. M. Ladomery proposes that a compre- problems for the organism. Indeed, the extreme flexibility hensive dysregulation of alternative splicing could, in itself, of its regulation, which relies on the combinatorial action be considered yet another hallmark of cancer. The idea is of multiple non stringent factors, is subject to errors and that the aberrant expression and activity of key oncogenic the aberrant splicing of key genes can result in the onset of splicing factors and/or their regulatory kinases could lead many human genetic and sporadic diseases. In this regard, to a systematic change in gene expression by favouring the mounting evidence illustrates how changes in alternative concurrent production of several oncogenic splice variants of splicing patterns of specific genes is an important tool used genes involved in critical biological aspects of tumour cells. by cancer cells to produce protein isoforms involved in all S. C. Lenzken et al. review our current knowledge of the areas of cancer cell biology, including numerous aspects of role of alternative splicing in the multiple and various aspects tumor establishment, progression, and resistance to thera- of the DNA damage response (DDR) and the control of peutic treatments. Importantly, cancer-specific splice variants genome stability. This review illustrates several mechanisms have the potential to become suitable therapeutic targets for through which pre-mRNA splicing and genomic stability can human cancer, as novel tools to correct splicing defects are influence each other and contribute to tumorigenesis. being developed and, in some cases, have entered clinical M.Romanoandcolleaguesdrawattentiontothefunction trials for other human diseases, such as spinal muscular that pseudoexons and pseudointrons can play directly in atrophy. Nevertheless, these findings are likely to represent cancer pathology. These sequences can be found in genes just the tip of the iceberg and important questions regarding that have well-established roles in cancer, including BRCA1, 2 International Journal of Cell Biology BRCA2, NF-1, and ATM. They describe the mechanisms the regulation of alternative splicing is likely to present through which pseudoexons and pseudointrons can be acti- novelopportunitiesinthediagnosis,prognosis,andtreat- vated or repressed. In addition, they discuss their potential ment of prostate cancer. S. Bonomi et al. deal with novel use as tumour biomarkers to provide a more detailed staging information on how alternative splice variants of many and grading of cancer. cancer-related genes can directly contribute to the oncogenic C. Naro and C. Sette discuss the key role that reversible phenotype, focusing on a number of processes involved in phosphorylation plays in the regulation of alternative splic- cancer progression, such as response to hypoxia, migra- ing. Both splice
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