TUMOR SUPPRESSOR GENES Edited by Yue Cheng Tumor Suppressor Genes Edited by Yue Cheng Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. 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Publishing Process Manager Molly Kaliman Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published January, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Tumor Suppressor Genes, Edited by Yue Cheng p. cm. ISBN 978-953-307-879-3 Contents Preface IX Tumor Suppressor Gene p16/INK4A/CDKN2A Chapter 1 and Its Role in Cell Cycle Exit, Differentiation, and Determination of Cell Fate 1 Payal Agarwal, Farruk Mohammad Lutful Kabir, Patricia DeInnocentes and Richard Curtis Bird Susceptibility of Epithelium to Chapter 2 PTEN-Deficient Tumorigenesis 35 Chun-Ming Chen, Tsai-Ling Lu, Fang-Yi Su and Li-Ru You Identification of Tumor Suppressor Genes Chapter 3 via Cell Fusion and Chromosomal Transfer 53 Hong Lok Lung, Arthur Kwok Leung Cheung, Josephine Mun Yee Ko, Yue Cheng and Maria Li Lung TP53 Gene Polymorphisms in Cancer Risk: Chapter 4 The Modulating Effect of Ageing, Ethnicity and TP53 Somatic Abnormalities 79 Evgeny V. Denisov, Nadezhda V. Cherdyntseva, Nicolay V. Litviakov, Elena A. Malinovskaya, Natalya N. Babyshkina, Valentina A. Belyavskaya and Mikhail I. Voevoda Epigenetics and Tumor Suppressor Genes 111 Chapter 5 MingZhou Guo, XueFeng Liu and WeiMin Zhang Therapeutic Targeting of p53-Mediated Apoptosis Chapter 6 Pathway in Head and Neck Squamous Cell Carcinomas: Current Progress and Challenges 129 Solachuddin Jauhari Arief Ichwan, Muhammad Taher Bakhtiar, Kiyoshi Ohtani and Masa-Aki Ikeda Signaling Mechanisms of Transforming Growth Chapter 7 Factor-β (TGF-β) in Cancer: TGF-β Induces Apoptosis in Lung Cells by a Smad-Dependent Mechanism 145 Mi Jung Lim, Tiffany Lin and Sonia B. Jakowlew VI Contents Refining the Role of Lgl, Dlg and Scrib Chapter 8 in Tumor Suppression and Beyond: Learning from the Old Time Classics 181 Fani Papagiannouli and Bernard M. Mechler Epigenetic and Posttranscriptional Alterations of Tumor Chapter 9 Suppressor Genes in Sporadic Pituitary Adenomas 221 Henriett Butz, Károly Rácz and Attila Patócs Genomic and Expression Alterations of Chapter 10 Tumor Suppressor Genes in Meningioma Development, Progression and Recurrence 247 E. Pérez-Magán, J.A. Rey, B. Meléndez and Javier S. Castresana Control of Retinal Development Chapter 11 by Tumor Suppressor Genes 269 Robert Cantrup, Gaurav Kaushik and Carol Schuurmans Properties of Human Tumor Suppressor Chapter 12 101F6 Protein as a Cytochrome b561 and Its Preliminary Crystallization Trials 295 Mariam C. Recuenco, Suguru Watanabe, Fusako Takeuchi, Sam-Yong Park and Motonari Tsubaki Epigenetic Control of Chapter 13 Tumor Suppressor Genes in Lung Cancer 309 Xuan Qiu, Roman Perez-Soler and Yiyu Zou Preface Tumor suppressor genes (TSGs) play critical roles in many biological processes, including cell cycle control, apoptosis, DNA repair, cell division and differentiation, tumor migration and metastasis, and reprogramming control of somatic cells. TSGs were named so because of their functional roles in original tumor growth control experiments. Early somatic cell fusion studies of malignant and nonmalignant cell provided the first evidence of a class of negatively acting TSGs, harbored on normal chromosomes that contrast to dominant-acting oncogenes, which play important roles in tumor suppression. The first TSG was isolated from retinoblastoma, although recent evidence has suggested that this gene is also a key regulator of normal developmental events, as addressed in this book. Other important TSGs, such as P53, P16 and PTEN, were subsequently identified based on “two-hit” hypothesis of TSGs as well. Underlying mechanisms of TSGs have been vigorously investigated over the past 30 years. This book covers the aspects of most fascinating fields, from cell cycle control, signaling pathways, gene dosage effects and epigenetic control of gene expression, to current challenges and future directions in TSG studies. Since tumor suppression is now a huge research field and many novel TSGs have been identified from various human malignancies, it is almost impossible to cover all interesting areas in just one book. As a classic TSG, P53 is addressed in this book because of its risk on polymorphism and its critical role in apoptosis pathways. P16 and its family that regulate cell cycle and determine cell fate are introduced and reviewed in detail. Some of the chapters focus on the epigenetic control of TSG, notably P16, in lung, pituitary tumors and meningioma. TSG studies in other models, such as transgenic mouse and Drosophila, are also included in this book. Studies on PTEN and other classic TSGs are described in these chapters well. The regulation of an important cellular signaling, TGF-beta, in lung cancer is presented in this book, and readers can find information on other signaling controls of carcinogenesis in different chapters. Furthermore, expression and purification of the human 101F6 protein, encoded by a candidate TSG on the chromosome 3p21.3, is presented as a crystallization trial example. Finally, one chapter discusses a classic approach using cell fusion and chromosome transfer to identify novel TSGs in nasopharyngeal carcinoma. X Preface A wide range of basic, translational, and clinical researches is leading the quest to find promising new ways to use these genes to suppress cancer. An example of such trails in head and neck cancer is presented in this book. Although we are not there yet, ongoing research efforts on TSGs, coupled with advances in gene therapy and other techniques, have the potential to open new avenues in the treatment of human tumors. We hope that this book will be helpful to both researchers and clinicians. Yue Cheng, PhD The University of Hong Kong China [...]... Benz, 1992) Defects in tumor suppressor genes and oncogenes result in uncontrolled cell division, which leads to cancer (Tripathy & Benz, 1992) Oncogenes are mutated proto-oncogenes that have a role in malignancy of tumors and most frequently regulate cell cycle re-entry Gain-of-function mutations result in transformation of proto-oncogenes into dominant oncogenes Tumor suppressor genes encode proteins... 1 Tumor Suppressor Gene p16/INK4A/CDKN2A and Its Role in Cell Cycle Exit, Differentiation, and Determination of Cell Fate Payal Agarwal, Farruk Mohammad Lutful Kabir, Patricia DeInnocentes and Richard Curtis Bird College of Veterinary Medicine, Auburn University, Auburn, Al USA 1 Introduction Tumor suppressor genes and oncogenes are important regulatory genes which encode proteins... and most frequently result in exit from the cell cycle Lossof-function mutations in tumor suppressor genes result in tumor malignancy and can account for hereditary cancers Every gene has two alleles present in the genome (with a few exceptions in the hemizygous regions of the sex chromosomes) For tumor suppressor genes to be inactivated either deletion of one allele and somatic mutation of the other... both of the alleles is required resulting in a complete loss of homozygosity (Quelle et al., 1997) Tumor suppressor genes can also be inactivated by hypermethylation of the gene resulting in promoter suppression so that genes can not be transcribed further (Herman et al., 1997) Telomere shortening and tumor suppressor gene promoter hyper-methylation can be used as potential breast cancer biomarkers (Radpour... (H3K27), bound to the 4 Tumor Suppressor Genes hTERT promoter (Bazarov et al., 2010) hTERT encodes the catalytic subunit of telomerase; therefore, p16 induction results in repression of telomerase and thus telomere shortening Another binding partner important for cell growth inhibition by p16 is GRIM-19 (Gene associated with Retinoid-IFN-induced Mortality-19) GRIM-19 is a tumor suppressor gene mutations... bound cyclin (Jeffrey et al., 2000) A lack of mutations in p18 and p19 has been reported in tumor- derived cell lines and primary tumors, which were mutated for p16 and p15 expression, which shows distinct biological function of evolutionary related INK4 proteins (Zariwala & Xiong, 1996) 8 Tumor Suppressor Genes The INK4 and CIP cyclin dependent kinase inhibitor families have overlapping roles of cell... inhibitory effects on cell growth of the human lung cancer cell line A549 (Zhang et al., 2010b) 3 The role of p16 3.1 p16 as a tumor suppressor gene CKI p16 is an important tumor suppressor gene, defects in which are associated with cancer (Koh et al., 1995) p16 is functional as a growth suppressor gene as introduction of full length p16 cDNA caused marked growth suprression in p16-null human glioma cells... polycomb protein from the INK4/ARF locus This leads to transcription and replication of the INK4/ARF locus 16 Tumor Suppressor Genes in early S phase prior to reaching senescence (Agherbi et al., 2009) CDC6 is an essential DNA replication regulator CDC6 overexpression induces increased INK4/ARF tumor suppressor gene expression through epigenetic modification of chromatin at the INK4/ARF locus (Borlado &... senescence prevent tumor progression during alternative colorectal tumorigenesis Cancer Cell, Vol 18, No.2, pp (135-146) 1878-3686 Boehme K.A & Blattner, C (2009) "Regulation of p53 insights into a complex process Crit Rev Biochem Mol Biol, Vol 44, No.6, pp (367-392) 1549-7798 Borlado L.R & Mendez, J (2008) "CDC6: from DNA replication to cell cycle checkpoints and oncogenesis Carcinogenesis, Vol 29,... to the P16 tumor suppressor protein Biochem Biophys Res Commun, Vol 249, No.2, pp (550-555) 0006-291X Chebel A., Chien, W.W., Gerland, L.M., Mekki, Y., Bertrand, Y., Ffrench, P., Galmarini, C.M & Ffrench, M (2007) "Does p16ink4a expression increase with the number of cell doublings in normal and malignant lymphocytes? Leuk Res, Vol 31, No.12, pp (1649-1658) 0145-2126 20 Tumor Suppressor Genes Chen . TUMOR SUPPRESSOR GENES Edited by Yue Cheng Tumor Suppressor Genes Edited by Yue Cheng Published by InTech Janeza. Epigenetic Control of Chapter 13 Tumor Suppressor Genes in Lung Cancer 309 Xuan Qiu, Roman Perez-Soler and Yiyu Zou Preface Tumor suppressor genes (TSGs) play critical roles. 1992). Defects in tumor suppressor genes and oncogenes result in uncontrolled cell division, which leads to cancer (Tripathy & Benz, 1992). Oncogenes are mutated proto-oncogenes that have