Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 798K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Okazaki, I.-m. Articles by Honjo, T. Search for Related Content PubMed PubMed Citation Articles by Okazaki, I.-m. Articles by Honjo, T. Social Bookmarking                            What's this?

Constitutive Expression of AID Leads to Tumorigenesis

Il-mi Okazaki¹, Hiroshi Hiai², Naoki Kakazu³, Shuichi Yamada⁴, Masamichi Muramatsu¹, Kazuo Kinoshita¹ and Tasuku Honjo¹

¹ Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
² Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
³ Department of Hygiene, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
⁴ Department of Cell Biology, Institute for Virus Research, Kyoto University, 53 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

Address correspondence to Tasuku Honjo, Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4371; Fax: 81-75-753-4388; E-mail: honjo{at}mfour.med.kyoto-u.ac.jp

Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy.

Key Words: class switch recombination • somatic hypermutation • genomic instability • lymphoma • T cell receptor gene

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Pauklin, S., Petersen-Mahrt, S. K. (2009). Progesterone Inhibits Activation-Induced Deaminase by Binding to the Promoter. J. Immunol. 183: 1238-1244 [Abstract] [Full Text]  
• Chiu, Y.-L., Greene, W. C (2009). APOBEC3G: an intracellular centurion. Phil Trans R Soc B 364: 689-703 [Abstract] [Full Text]  
• Pauklin, S., Sernandez, I. V., Bachmann, G., Ramiro, A. R., Petersen-Mahrt, S. K. (2009). Estrogen directly activates AID transcription and function. JEM 206: 99-111 [Abstract] [Full Text]  
• Wu, X., Darce, J. R., Chang, S. K., Nowakowski, G. S., Jelinek, D. F. (2008). Alternative splicing regulates activation-induced cytidine deaminase (AID): implications for suppression of AID mutagenic activity in normal and malignant B cells. Blood 112: 4675-4682 [Abstract] [Full Text]  
• Kinoshita, S. M., Taguchi, S. (2008). NF-IL6 (C/EBP{beta}) induces HIV-1 replication by inhibiting cytidine deaminase APOBEC3G. Proc. Natl. Acad. Sci. USA 105: 15022-15027 [Abstract] [Full Text]  
• Takizawa, M., Tolarova, H., Li, Z., Dubois, W., Lim, S., Callen, E., Franco, S., Mosaico, M., Feigenbaum, L., Alt, F. W., Nussenzweig, A., Potter, M., Casellas, R. (2008). AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development. JEM 205: 1949-1957 [Abstract] [Full Text]  
• Aoufouchi, S., Faili, A., Zober, C., D'Orlando, O., Weller, S., Weill, J.-C., Reynaud, C.-A. (2008). Proteasomal degradation restricts the nuclear lifespan of AID. JEM 205: 1357-1368 [Abstract] [Full Text]  
• Bennett, R. P., Presnyak, V., Wedekind, J. E., Smith, H. C. (2008). Nuclear Exclusion of the HIV-1 Host Defense Factor APOBEC3G Requires a Novel Cytoplasmic Retention Signal and Is Not Dependent on RNA Binding. J. Biol. Chem. 283: 7320-7327 [Abstract] [Full Text]  
• Lin, W., Hashimoto, S.-i., Seo, H., Shibata, T., Ohta, K. (2008). Modulation of immunoglobulin gene conversion frequency and distribution by the histone deacetylase HDAC2 in chicken DT40.. GENES CELLS 13: 255-268 [Abstract] [Full Text]  
• Janas, M. L., Hodson, D., Stamataki, Z., Hill, S., Welch, K., Gambardella, L., Trotman, L. C., Pandolfi, P. P., Vigorito, E., Turner, M. (2008). The Effect of Deleting p110{delta} on the Phenotype and Function of PTEN-Deficient B Cells. J. Immunol. 180: 739-746 [Abstract] [Full Text]  
• Perez-Duran, P., de Yebenes, V. G., Ramiro, A. R. (2007). Oncogenic events triggered by AID, the adverse effect of antibody diversification. Carcinogenesis 28: 2427-2433 [Abstract] [Full Text]  
• Chatterji, M., Unniraman, S., McBride, K. M., Schatz, D. G. (2007). Role of Activation-Induced Deaminase Protein Kinase A Phosphorylation Sites in Ig Gene Conversion and Somatic Hypermutation. J. Immunol. 179: 5274-5280 [Abstract] [Full Text]  
• Blanc, V., Henderson, J. O., Newberry, R. D., Xie, Y., Cho, S.-J., Newberry, E. P., Kennedy, S., Rubin, D. C., Wang, H. L., Luo, J., Davidson, N. O. (2007). Deletion of the AU-Rich RNA Binding Protein Apobec-1 Reduces Intestinal Tumor Burden in Apcmin Mice. Cancer Res. 67: 8565-8573 [Abstract] [Full Text]  
• Dorsett, Y., Robbiani, D. F., Jankovic, M., Reina-San-Martin, B., Eisenreich, T. R., Nussenzweig, M. C. (2007). A role for AID in chromosome translocations between c-myc and the IgH variable region. JEM 204: 2225-2232 [Abstract] [Full Text]  
• Crouch, E. E., Li, Z., Takizawa, M., Fichtner-Feigl, S., Gourzi, P., Montano, C., Feigenbaum, L., Wilson, P., Janz, S., Papavasiliou, F. N., Casellas, R. (2007). Regulation of AID expression in the immune response. JEM 204: 1145-1156 [Abstract] [Full Text]  
• Feldhahn, N., Henke, N., Melchior, K., Duy, C., Soh, B. N., Klein, F., von Levetzow, G., Giebel, B., Li, A., Hofmann, W.-K., Jumaa, H., Muschen, M. (2007). Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells. JEM 204: 1157-1166 [Abstract] [Full Text]  
• Hsu, H.-C., Wu, Y., Yang, P., Wu, Q., Job, G., Chen, J., Wang, J., Accavitti-Loper, M. A. V., Grizzle, W. E., Carter, R. H., Mountz, J. D. (2007). Overexpression of Activation-Induced Cytidine Deaminase in B Cells Is Associated with Production of Highly Pathogenic Autoantibodies. J. Immunol. 178: 5357-5365 [Abstract] [Full Text]  
• Gourzi, P., Leonova, T., Papavasiliou, F. N. (2007). Viral induction of AID is independent of the interferon and the Toll-like receptor signaling pathways but requires NF-{kappa}B. JEM 204: 259-265 [Abstract] [Full Text]  
• Kotani, A., Kakazu, N., Tsuruyama, T., Okazaki, I.-m., Muramatsu, M., Kinoshita, K., Nagaoka, H., Yabe, D., Honjo, T. (2007). Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice. Proc. Natl. Acad. Sci. USA 104: 1616-1620 [Abstract] [Full Text]  
• Tobollik, S., Meyer, L., Buettner, M., Klemmer, S., Kempkes, B., Kremmer, E., Niedobitek, G., Jungnickel, B. (2006). Epstein-Barr virus nuclear antigen 2 inhibits AID expression during EBV-driven B-cell growth. Blood 108: 3859-3864 [Abstract] [Full Text]  
• Shen, R. R., Ferguson, D. O., Renard, M., Hoyer, K. K., Kim, U., Hao, X., Alt, F. W., Roeder, R. G., Morse, H. C. III, Teitell, M. A. (2006). Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation. Blood 108: 1991-1998 [Abstract] [Full Text]  
• McBride, K. M., Gazumyan, A., Woo, E. M., Barreto, V. M., Robbiani, D. F., Chait, B. T., Nussenzweig, M. C. (2006). Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc. Natl. Acad. Sci. USA 103: 8798-8803 [Abstract] [Full Text]  
• Babbage, G., Ottensmeier, C. H., Blaydes, J., Stevenson, F. K., Sahota, S. S. (2006). Immunoglobulin heavy chain locus events and expression of activation-induced cytidine deaminase in epithelial breast cancer cell lines.. Cancer Res. 66: 3996-4000 [Abstract] [Full Text]  
• Chiu, Y.-L., Greene, W. C. (2006). APOBEC3 Cytidine Deaminases: Distinct Antiviral Actions along the Retroviral Life Cycle. J. Biol. Chem. 281: 8309-8312 [Abstract] [Full Text]  
• Muto, T., Okazaki, I.-m., Yamada, S., Tanaka, Y., Kinoshita, K., Muramatsu, M., Nagaoka, H., Honjo, T. (2006). Negative regulation of activation-induced cytidine deaminase in B cells. Proc. Natl. Acad. Sci. USA 103: 2752-2757 [Abstract] [Full Text]  
• Wakae, K., Magor, B. G., Saunders, H., Nagaoka, H., Kawamura, A., Kinoshita, K., Honjo, T., Muramatsu, M. (2006). Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID. Int Immunol 18: 41-47 [Abstract] [Full Text]  
• Rush, J. S., Liu, M., Odegard, V. H., Unniraman, S., Schatz, D. G. (2005). Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proc. Natl. Acad. Sci. USA 102: 13242-13247 [Abstract] [Full Text]  
• Ronai, D., Iglesias-Ussel, M. D., Fan, M., Shulman, M. J., Scharff, M. D. (2005). Complex regulation of somatic hypermutation by cis-acting sequences in the endogenous IgH gene in hybridoma cells. Proc. Natl. Acad. Sci. USA 102: 11829-11834 [Abstract] [Full Text]  
• Machida, K., Cheng, K. T.-H., Pavio, N., Sung, V. M.-H., Lai, M. M. C. (2005). Hepatitis C Virus E2-CD81 Interaction Induces Hypermutation of the Immunoglobulin Gene in B Cells. J. Virol. 79: 8079-8089 [Abstract] [Full Text]  
• Martomo, S. A., Fu, D., Yang, W. W., Joshi, N. S., Gearhart, P. J. (2005). Deoxyuridine Is Generated Preferentially in the Nontranscribed Strand of DNA from Cells Expressing Activation-Induced Cytidine Deaminase. J. Immunol. 174: 7787-7791 [Abstract] [Full Text]  
• Kotani, A., Okazaki, I.-m., Muramatsu, M., Kinoshita, K., Begum, N. A., Nakajima, T., Saito, H., Honjo, T. (2005). A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression. Proc. Natl. Acad. Sci. USA 102: 4506-4511 [Abstract] [Full Text]  
• Wilson, T. M., Vaisman, A., Martomo, S. A., Sullivan, P., Lan, L., Hanaoka, F., Yasui, A., Woodgate, R., Gearhart, P. J. (2005). MSH2-MSH6 stimulates DNA polymerase {eta}, suggesting a role for A:T mutations in antibody genes. JEM 201: 637-645 [Abstract] [Full Text]  
• Morgan, H. D., Dean, W., Coker, H. A., Reik, W., Petersen-Mahrt, S. K. (2004). Activation-induced Cytidine Deaminase Deaminates 5-Methylcytosine in DNA and Is Expressed in Pluripotent Tissues: IMPLICATIONS FOR EPIGENETIC REPROGRAMMING. J. Biol. Chem. 279: 52353-52360 [Abstract] [Full Text]  
• Zhang, J. Q., Okumura, C., McCarty, T., Shin, M. S., Mukhopadhyay, P., Hori, M., Torrey, T. A., Naghashfar, Z., Zhou, J. X., Lee, C. H., Roopenian, D. C., Morse, H. C. III, Davidson, W. F. (2004). Evidence for Selective Transformation of Autoreactive Immature Plasma Cells in Mice Deficient in Fasl. JEM 200: 1467-1478 [Abstract] [Full Text]  
• Rose, K. M., Marin, M., Kozak, S. L., Kabat, D. (2004). Transcriptional Regulation of APOBEC3G, a Cytidine Deaminase That Hypermutates Human Immunodeficiency Virus. J. Biol. Chem. 279: 41744-41749 [Abstract] [Full Text]  
• Martomo, S. A., Yang, W. W., Gearhart, P. J. (2004). A Role for Msh6 But Not Msh3 in Somatic Hypermutation and Class Switch Recombination. JEM 200: 61-68 [Abstract] [Full Text]  
• Brar, S. S., Watson, M., Diaz, M. (2004). Activation-induced Cytosine Deaminase (AID) Is Actively Exported out of the Nucleus but Retained by the Induction of DNA Breaks. J. Biol. Chem. 279: 26395-26401 [Abstract] [Full Text]  
• Cascalho, M. (2004). Advantages and Disadvantages of Cytidine Deamination. J. Immunol. 172: 6513-6518 [Abstract] [Full Text]  
• Wang, C. L., Harper, R. A., Wabl, M. (2004). Genome-wide somatic hypermutation. Proc. Natl. Acad. Sci. USA 101: 7352-7356 [Abstract] [Full Text]  
• Kenter, A. L., Wuerffel, R., Dominguez, C., Shanmugam, A., Zhang, H. (2004). Mapping of a Functional Recombination Motif that Defines Isotype Specificity for {micro}->{gamma}3 Switch Recombination Implicates NF-{kappa}B p50 as the Isotype-specific Switching Factor. JEM 199: 617-627 [Abstract] [Full Text]  
• He, B., Chadburn, A., Jou, E., Schattner, E. J., Knowles, D. M., Cerutti, A. (2004). Lymphoma B Cells Evade Apoptosis through the TNF Family Members BAFF/BLyS and APRIL. J. Immunol. 172: 3268-3279 [Abstract] [Full Text]  
• Ito, S., Nagaoka, H., Shinkura, R., Begum, N., Muramatsu, M., Nakata, M., Honjo, T. (2004). Activation-induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1. Proc. Natl. Acad. Sci. USA 101: 1975-1980 [Abstract] [Full Text]  
• Albesiano, E., Messmer, B. T., Damle, R. N., Allen, S. L., Rai, K. R., Chiorazzi, N. (2003). Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 102: 3333-3339 [Abstract] [Full Text]  
• Eto, T., Kinoshita, K., Yoshikawa, K., Muramatsu, M., Honjo, T. (2003). RNA-editing cytidine deaminase Apobec-1 is unable to induce somatic hypermutation in mammalian cells. Proc. Natl. Acad. Sci. USA 100: 12895-12898 [Abstract] [Full Text]  
• Smit, L. A., Bende, R. J., Aten, J., Guikema, J. E. J., Aarts, W. M., van Noesel, C. J. M. (2003). Expression of Activation-induced Cytidine Deaminase Is Confined to B-Cell Non-Hodgkin's Lymphomas of Germinal-Center Phenotype. Cancer Res. 63: 3894-3898 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS