Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Repression of human activation induced cytidine deaminase by miR-93 and miR-155

Authors: Glen M Borchert, Nathaniel W Holton, Erik D Larson

Published in: BMC Cancer | Issue 1/2011

Login to get access

Abstract

Background

Activation Induced cytidine Deaminase (AID) targets the immunoglobulin genes of activated B cells, where it converts cytidine to uracil to induce mutagenesis and recombination. While essential for immunoglobulin gene diversification, AID misregulation can result in genomic instability and oncogenic transformation. This is classically illustrated in Burkitt's lymphoma, which is characterized by AID-induced mutation and reciprocal translocation of the c-MYC oncogene with the IgH loci. Originally thought to be B cell-specific, AID now appears to be misexpressed in several epithelial cancers, raising the specter that AID may also participate in non-B cell carcinogenesis.

Methods

The mutagenic potential of AID argues for the existence of cellular regulators capable of repressing inappropriate AID expression. MicroRNAs (miRs) have this capacity, and we have examined the publically available human AID EST dataset for miR complementarities to the human AID 3'UTR. In this work, we have evaluated the capacity of two candidate miRs to repress human AID expression in MCF-7 breast carcinoma cells.

Results

We have discovered moderate miR-155 and pronounced miR-93 complementary target sites encoded within the human AID mRNA. Luciferase reporter assays indicate that both miR-93 and miR-155 can interact with the 3'UTR of AID to block expression. In addition, over-expression of either miR in MCF-7 cells reduces endogenous AID protein, but not mRNA, levels. Similarly indicative of AID translational regulation, depletion of either miR in MCF-7 cells increases AID protein levels without concurrent increases in AID mRNA.

Conclusions

Together, our findings demonstrate that miR-93 and miR-155 constitutively suppress AID translation in MCF-7 cells, suggesting widespread roles for these miRs in preventing genome cytidine deaminations, mutagenesis, and oncogenic transformation. In addition, our characterization of an obscured miR-93 target site located within the AID 3'UTR supports the recent suggestion that many miR regulations have been overlooked due to the prevalence of truncated 3'UTR annotations.
Appendix
Available only for authorised users
Literature
1.
de Yebenes VG, Ramiro AR: Activation-induced deaminase: light and dark sides. Trends Mol Med. 2006, 12: 432-439. 10.1016/j.molmed.2006.07.001.CrossRefPubMed
2.
Goodman MF, Scharff MD, Romesberg FE: AID-initiated purposeful mutations in immunoglobulin genes. Adv Immunol. 2007, 94: 127-155.CrossRefPubMed
3.
Longerich S, Basu U, Alt F, Storb U: AID in somatic hypermutation and class switch recombination. Curr Opin Immunol. 2006, 18: 164-174. 10.1016/j.coi.2006.01.008.CrossRefPubMed
4.
Peled JU, Kuang FL, Iglesias-Ussel MD, Roa S, Kalis SL, Goodman MF, Scharff MD: The biochemistry of somatic hypermutation. Annu Rev Immunol. 2008, 26: 481-511. 10.1146/annurev.immunol.26.021607.090236.CrossRefPubMed
5.
Vallur AC, Yabuki M, Larson ED, Maizels N: AID in antibody perfection. Cell Mol Life Sci. 2007, 64: 555-565. 10.1007/s00018-007-6434-2.CrossRefPubMed
6.
Larson ED, Bednarski DW, Maizels N: High-fidelity correction of genomic uracil by human mismatch repair activities. BMC Mol Biol. 2008, 9: 94-10.1186/1471-2199-9-94.CrossRefPubMedPubMedCentral
7.
Stavnezer J, Guikema JE, Schrader CE: Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008, 26: 261-292. 10.1146/annurev.immunol.26.021607.090248.CrossRefPubMedPubMedCentral
8.
Liu M, Schatz DG: Balancing AID and DNA repair during somatic hypermutation. Trends Immunol. 2009, 30: 173-181. 10.1016/j.it.2009.01.007.CrossRefPubMed
9.
Perez-Duran P, de Yebenes VG, Ramiro AR: Oncogenic events triggered by AID, the adverse effect of antibody diversification. Carcinogenesis. 2007, 28: 2427-2433. 10.1093/carcin/bgm201.CrossRefPubMed
10.
Yamane A, Resch W, Kuo N, Kuchen S, Li Z, Sun HW, Robbiani DF, McBride K, Nussenzweig MC, Casellas R: Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nat Immunol. 2011, 12: 62-69. 10.1038/ni.1964.CrossRefPubMed
11.
Staszewski O, Baker RE, Ucher AJ, Martier R, Stavnezer J, Guikema JE: Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells. Mol Cell. 2011, 41: 232-242. 10.1016/j.molcel.2011.01.007.CrossRefPubMedPubMedCentral
12.
Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, Schatz DG: Two levels of protection for the B cell genome during somatic hypermutation. Nature. 2008, 451: 841-845. 10.1038/nature06547.CrossRefPubMed
13.
Nagaoka H, Tran TH, Kobayashi M, Aida M, Honjo T: Preventing AID, a physiological mutator, from deleterious activation: regulation of the genomic instability that is associated with antibody diversity. Int Immunol. 2010, 22: 227-235. 10.1093/intimm/dxq023.CrossRefPubMed
14.
Okazaki IM, Hiai H, Kakazu N, Yamada S, Muramatsu M, Kinoshita K, Honjo T: Constitutive expression of AID leads to tumorigenesis. J Exp Med. 2003, 197: 1173-1181. 10.1084/jem.20030275.CrossRefPubMedPubMedCentral
15.
Parsa JY, Basit W, Wang CL, Gommerman JL, Carlyle JR, Martin A: AID mutates a non-immunoglobulin transgene independent of chromosomal position. Mol Immunol. 2007, 44: 567-575. 10.1016/j.molimm.2006.02.003.CrossRefPubMed
16.
Zhang W, Bardwell PD, Woo CJ, Poltoratsky V, Scharff MD, Martin A: Clonal instability of V region hypermutation in the Ramos Burkitt's lymphoma cell line. Int Immunol. 2001, 13: 1175-1184. 10.1093/intimm/13.9.1175.CrossRefPubMed
17.
Rossi D, Berra E, Cerri M, Deambrogi C, Barbieri C, Franceschetti S, Lunghi M, Conconi A, Paulli M, Matolcsy A, Pasqualucci L, Capello D, Gaidano G: Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma. Haematologica. 2006, 91: 1405-1409.PubMed
18.
Casellas R, Yamane A, Kovalchuk AL, Potter M: Restricting activation-induced cytidine deaminase tumorigenic activity in B lymphocytes. Immunology. 2009, 126: 316-328. 10.1111/j.1365-2567.2008.03050.x.CrossRefPubMedPubMedCentral
19.
Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, Muramatsu M, Honjo T, Nussenzweig A, Nussenzweig MC: AID is required for c-myc/IgH chromosome translocations in vivo. Cell. 2004, 118: 431-438. 10.1016/j.cell.2004.08.006.CrossRefPubMed
20.
Robbiani DF, Bothmer A, Callen E, Reina-San-Martin B, Dorsett Y, Difilippantonio S, Bolland DJ, Chen HT, Corcoran AE, Nussenzweig A, Nussenzweig MC: AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell. 2008, 135: 1028-1038. 10.1016/j.cell.2008.09.062.CrossRefPubMedPubMedCentral
21.
Endo Y, Marusawa H, Chiba T: Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers. J Gastroenterol. 2011, 46 (Suppl 1): 6-10.CrossRefPubMed
22.
Matsumoto Y, Marusawa H, Kinoshita K, Niwa Y, Sakai Y, Chiba T: Up-regulation of activation-induced cytidine deaminase causes genetic aberrations at the CDKN2b-CDKN2a in gastric cancer. Gastroenterology. 2010, 139: 1984-1994. 10.1053/j.gastro.2010.07.010.CrossRefPubMed
23.
Shinmura K, Igarashi H, Goto M, Tao H, Yamada H, Matsuura S, Tajima M, Matsuda T, Yamane A, Funai K, Tanahashi M, Niwa H, Ogawa H, Sugimura H: Aberrant Expression and Mutation-Inducing Activity of AID in Human Lung Cancer. Ann Surg Oncol. 2011
24.
Babbage G, Ottensmeier CH, Blaydes J, Stevenson FK, Sahota SS: Immunoglobulin heavy chain locus events and expression of activation-induced cytidine deaminase in epithelial breast cancer cell lines. Cancer Res. 2006, 66: 3996-4000. 10.1158/0008-5472.CAN-05-3704.CrossRefPubMed
25.
Pauklin S, Sernandez IV, Bachmann G, Ramiro AR, Petersen-Mahrt SK: Estrogen directly activates AID transcription and function. J Exp Med. 2009, 206: 99-111. 10.1084/jem.20080521.CrossRefPubMedPubMedCentral
26.
Lau NC, Lim LP, Weinstein EG, Bartel DP: An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001, 294: 858-862. 10.1126/science.1065062.CrossRefPubMed
27.
Lee RC, Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001, 294: 862-864. 10.1126/science.1065329.CrossRefPubMed
28.
Farazi TA, Spitzer JI, Morozov P, Tuschl T: miRNAs in human cancer. J Pathol. 2011, 223: 102-115. 10.1002/path.2806.CrossRefPubMed
29.
Dorsett Y, McBride KM, Jankovic M, Gazumyan A, Thai TH, Robbiani DF, Di Virgilio M, San-Martin BR, Heidkamp G, Schwickert TA, Eisenreich T, Rajewsky K, Nussenzweig MC: MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity. 2008, 28: 630-638. 10.1016/j.immuni.2008.04.002.CrossRefPubMedPubMedCentral
30.
Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R, Papavasiliou FN: MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity. 2008, 28: 621-629. 10.1016/j.immuni.2008.03.015.CrossRefPubMedPubMedCentral
31.
Kluiver J, Haralambieva E, de Jong D, Blokzijl T, Jacobs S, Kroesen BJ, Poppema S, van den Berg A: Lack of BIC and microRNA miR-155 expression in primary cases of Burkitt lymphoma. Genes Chromosomes Cancer. 2006, 45: 147-153. 10.1002/gcc.20273.CrossRefPubMed
32.
Borchert GM, Lanier W, Davidson BL: RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol. 2006, 13: 1097-1101. 10.1038/nsmb1167.CrossRefPubMed
33.
Sale JE, Neuberger MS: TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity. 1998, 9: 859-869. 10.1016/S1074-7613(00)80651-2.CrossRefPubMed
34.
Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M, et al: A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 2007, 129: 1401-1414. 10.1016/j.cell.2007.04.040.CrossRefPubMedPubMedCentral
35.
Ebert MS, Neilson JR, Sharp PA: MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007, 4: 721-726. 10.1038/nmeth1079.CrossRefPubMed
36.
37.
Long J, Wang Y, Wang W, Chang BH, Danesh FR: Identification of microRNA-93 as a novel regulator of vascular endothelial growth factor in hyperglycemic conditions. J Biol Chem. 2010, 285: 23457-23465. 10.1074/jbc.M110.136168.CrossRefPubMedPubMedCentral
38.
Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A: E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008, 13: 272-286. 10.1016/j.ccr.2008.02.013.CrossRefPubMed
39.
Du L, Schageman JJ, Subauste MC, Saber B, Hammond SM, Prudkin L, Wistuba II, Ji L, Roth JA, Minna JD, Pertsemlidis A: miR-93, miR-98, and miR-197 regulate expression of tumor suppressor gene FUS1. Mol Cancer Res. 2009, 7: 1234-1243. 10.1158/1541-7786.MCR-08-0507.CrossRefPubMedPubMedCentral
40.
Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, Yee AJ, Ang LC, He C, Shan SW, Yang BB: MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-beta8. Oncogene. 2011, 30: 806-821. 10.1038/onc.2010.465.CrossRefPubMed
41.
Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, Hur K, Yoo MW, Lee HJ, Yang HK, Kim VN: Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res. 2009, 37: 1672-1681. 10.1093/nar/gkp002.CrossRefPubMedPubMedCentral
42.
Yeung ML, Yasunaga J, Bennasser Y, Dusetti N, Harris D, Ahmad N, Matsuoka M, Jeang KT: Roles for microRNAs, miR-93 and miR-130b, and tumor protein 53-induced nuclear protein 1 tumor suppressor in cell growth dysregulation by human T-cell lymphotrophic virus 1. Cancer Res. 2008, 68: 8976-8985. 10.1158/0008-5472.CAN-08-0769.CrossRefPubMedPubMedCentral
43.
Djebali S, Kapranov P, Foissac S, Lagarde J, Reymond A, Ucla C, Wyss C, Drenkow J, Dumais E, Murray RR, Lin C, Szeto D, Denoeud F, Calvo M, Frankish A, Harrow J, Makrythanasis P, Vidal M, Salehi-Ashtiani K, Antonarakis SE, Gingeras TR, Guigo R: Efficient targeted transcript discovery via array-based normalization of RACE libraries. Nat Methods. 2008, 5: 629-635. 10.1038/nmeth.1216.CrossRefPubMedPubMedCentral
44.
Thorrez L, Tranchevent LC, Chang HJ, Moreau Y, Schuit F: Detection of novel 3' untranslated region extensions with 3' expression microarrays. BMC Genomics. 2010, 11: 205-10.1186/1471-2164-11-205.CrossRefPubMedPubMedCentral
45.
Borchert GM, Gilmore BL, Spengler RM, Xing Y, Lanier W, Bhattacharya D, Davidson BL: Adenosine deamination in human transcripts generates novel microRNA binding sites. Hum Mol Genet. 2009, 18: 4801-4807. 10.1093/hmg/ddp443.CrossRefPubMedPubMedCentral
46.
Hasler J, Samuelsson T, Strub K: Useful 'junk': Alu RNAs in the human transcriptome. Cell Mol Life Sci. 2007, 64: 1793-1800. 10.1007/s00018-007-7084-0.CrossRefPubMed
47.
Jurka J, Gentles AJ: Origin and diversification of minisatellites derived from human Alu sequences. Gene. 2006, 365: 21-26.CrossRefPubMed
48.
Lehnert S, Van Loo P, Thilakarathne PJ, Marynen P, Verbeke G, Schuit FC: Evidence for co-evolution between human microRNAs and Alu-repeats. PLoS One. 2009, 4: e4456-10.1371/journal.pone.0004456.CrossRefPubMedPubMedCentral
49.
Mighell AJ, Markham AF, Robinson PA: Alu sequences. FEBS Lett. 1997, 417: 1-5. 10.1016/S0014-5793(97)01259-3.CrossRefPubMed
50.
Smalheiser NR, Torvik VI: Alu elements within human mRNAs are probable microRNA targets. Trends Genet. 2006, 22: 532-536. 10.1016/j.tig.2006.08.007.CrossRefPubMed
51.
Yulug IG, Yulug A, Fisher EM: The frequency and position of Alu repeats in cDNAs, as determined by database searching. Genomics. 1995, 27: 544-548. 10.1006/geno.1995.1090.CrossRefPubMed
Metadata
Title
Repression of human activation induced cytidine deaminase by miR-93 and miR-155
Authors
Glen M Borchert
Nathaniel W Holton
Erik D Larson
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-347

Other articles of this Issue 1/2011

BMC Cancer 1/2011 Go to the issue

Research article

Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

Research article

Activating mutation in MET oncogene in familial colorectal cancer

Research article

A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation

Research article

Human cancer cells express Slug-based epithelial-mesenchymal transition gene expression signature obtained in vivo

Research article

Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma

Research article

Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits