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Analysis of ataxia-telangiectasia mutated (ATM)- and Nijmegen breakage syndrome (NBS)-regulated gene expression patterns

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Abstract

Purpose

Ataxia-telangiectasia (A-T) is a progressive, degenerative, complex autosomal recessive disease characterized by cerebellar degeneration, immunodeficiency, premature aging, radiosensitivity, and a predisposition to cancer. Mutations in the ataxia-telangiectasia mutated (atm) gene, which phosphorylates downstream effector proteins, are linked to A-T. One of the proteins phosphorylated by the ATM protein is Nijmegen Breakage Syndrome protein (NBS, p95/nibrin), which was recently shown to be encoded by a gene mutated in the Nijmegen breakage syndrome (nbs), an autosomal recessive disease with a phenotype virtually similar to that of A-T. The similarities in the clinical and cellular features of NBS and A-T have led us to hypothesize that the two corresponding gene products may function in similar ways in the cellular signaling pathway. Thus, we sought to identify genes whose expression is mediated by the atm and nbs gene products.

Material and methods

To identify genes, we performed an analysis of oligonucleotide microarrays using the appropriate cell lines, isogenic A-T (ATM-) and control cells (ATM+), and isogenic NBS (NBS-) and control cells (NBS+).

Results

We examined genes regulated by ATM and NBS, respectively. To determine the effect of ATM and NBS on gene expression in detail, we classified these genes into different functional categories, including those involved in apoptosis, cell cycle/DNA replication, growth/differentiation, signal transduction, cell-cell adhesion, and metabolism. In addition, we compared the genes regulated by the ATM and NBS to determine the relationship of their signaling pathways and to better understand their functional relationship.

Conclusions

We found that, while ATM and NBS regulate several genes in common, both of these proteins also have distinct patterns of gene regulation, findings consistent with the functional overlap and distinctiveness of these two conditions. Due to the role of ATM and NBS in tumor suppression and the response to chemotherapy and radiotherapy, these findings may assist in the development of a more rational approach to cancer treatment, as well as a better understanding of tumorigenesis.

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References

  • Blasina A, Price BD, Turenne GA, McGowan CH (1999) Caffeine inhibits the checkpoint kinase ATM. Curr Biol 9:1135–1138

    Article  CAS  PubMed  Google Scholar 

  • Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486

    CAS  PubMed  Google Scholar 

  • Chehab NH, Malikzay A, Appel M, Halazonetis TD (2000) Chk2/hCds1 functions as a DNA damage checkpoint in G1 by stabilizing p53. Genes Dev 14:278–288

    CAS  PubMed  Google Scholar 

  • Cortez D, Guntuku S, Qin J, Elledge SJ (2001) ATR and ATRIP: Partners in checkpoint signaling. Science 294:1713–1716

    Article  CAS  PubMed  Google Scholar 

  • Croxal JD, Newman SP, Choudhury Q, Flower RJ (1996) The concerted regulation of cPLA2, COX2, and lipocortin 1 expression by IL-1 beta in A 549 cells. Biochem Biophys Res Commun 220:491–495

    Article  PubMed  Google Scholar 

  • D’Amours D, Jackson SP (2002) The Mre11 complex: at the crossroads of DNA repair and checkpoint signaling. Nat Rev Mol Cell Biol 3:317–327

    Article  CAS  PubMed  Google Scholar 

  • Elledge SJ (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274:1664–1672

    CAS  PubMed  Google Scholar 

  • Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410:842–847

    Article  CAS  PubMed  Google Scholar 

  • Falck J, Petrini JH, Williams BR, Lukas J, Bartek J (2002) The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat Genet 30:290–294

    Article  PubMed  Google Scholar 

  • Gatei M, Young D, Cerosaletti KM, Desai-Mehta A, Spring K, Kozlov S, Lavin MF, Gatti RA, Concannon P, Khanna K (2000) ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nat Genet 25:115–119

    Article  CAS  PubMed  Google Scholar 

  • Gronbaek K, Worm J, Ralfkiaer E, Ahrenkiel V, Hokland P, Guldberg P (2002) ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma. Blood 100:1430–1437

    Article  CAS  PubMed  Google Scholar 

  • Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287:1824–1827

    Article  CAS  PubMed  Google Scholar 

  • Kastan MB, Lim DS (2000) The many substrates and functions of ATM. Nat Rev Mol Cell Biol 1:179–186

    CAS  PubMed  Google Scholar 

  • Kobuke K, Furukawa Y, Sugai M, Tanigaki K, Ohashi N, Matsumori A, Sasayama S, Honjo T, Tashiro K (2001) ESDN, a novel neuropilin-like membrane protein cloned from vascular cells with the longest secretory signal sequence among eukaryotes, is up-regulated after vascular injury. J Biol Chem 276:34105–34114

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Xu B, Lee CH, Ahn JY, Song MS, Lee H, Canman CE, Lee JS, Kastan MB, Lim DS (2003) Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. Mol Cancer Res 1:674–681

    CAS  PubMed  Google Scholar 

  • Levenson AS, Svoboda KM, Pease KM, Kaiser SA, Chen B, Simons LA, Jovanovic BD, Dyck PA, Jordan VC (2002) Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor. Cancer Res 62:4419–4426

    Google Scholar 

  • Lim DS, Kim ST, Xu B, Maser RS, Lin J, Petrini JH, Kastan MB (2000) ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404:613–617

    Article  CAS  PubMed  Google Scholar 

  • Marrogi A, Pass HI, Khan M, Metheny-Barlow LJ, Harris CC, Gerwin BI (2000) Human mesothelioma samples overexpress both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2): in vitro antiproliferative effects of a COX-2 inhibitor. Cancer Res 60:3696–3700

    CAS  PubMed  Google Scholar 

  • Matsuoka S, Huang M, Elledge SJ (1998) Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282:1893–1897

    CAS  PubMed  Google Scholar 

  • Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci USA 97:10389–10394

    Article  CAS  PubMed  Google Scholar 

  • Matsuura K, Balmukhanov T, Tauchi H, Weemaes C, Smeets D, Chrzanowska K, Endou S, Matsuura S, Komatsu K (1998) Radiation induction of p53 in cells from Nijmegen breakage syndrome is defective but not similar to ataxia-telangiectasia. Biochem Biophys Res Commun 242:602–607

    Article  CAS  PubMed  Google Scholar 

  • Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, Moas M, Buschmann T, Ronai Z, Shiloh Y, Kastan MB, Katzir E, Oren M (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15:1067–1077

    Article  CAS  PubMed  Google Scholar 

  • Otsuka M, Aizaki H, Kato N, Suzuki T, Miyamura T, Omata M, Seki N (2003) Differential cellular gene expression induced by hepatitis B and C viruses. Biochem Biophys Res Commun 300:443–447

    Article  CAS  PubMed  Google Scholar 

  • Petrini JH (1999) The mammalian Mre11-Rad50-nbs1 protein complex: integration of functions in the cellular DNA-damage response. Am J Hum Genet 64:1264–1269

    Article  CAS  PubMed  Google Scholar 

  • Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, Diederich S (2003) The human kidney is a progesterone-metabolizing and androgen-producing organ. J Clin Endocrinol Metab 88:2803–2809

    Article  CAS  PubMed  Google Scholar 

  • Reddy JA, Haneline LS, Srour EF, Antony AC, Clapp DW, Low PS (1999) Expression and functional characterization of the beta-isoform of the folate receptor on CD34(+) cells. Blood 93:3940–3948

    CAS  PubMed  Google Scholar 

  • Rouse J, Jackson SP (2002) Interfaces between the detection, signaling, and repair of DNA damage. Science 297:547–551

    Article  CAS  PubMed  Google Scholar 

  • Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14:289–300

    CAS  PubMed  Google Scholar 

  • Shiloh Y (1997) Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet 31:635–662

    Article  CAS  PubMed  Google Scholar 

  • Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanova E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93:467–476

    CAS  PubMed  Google Scholar 

  • Wu X, Ranganathan V, Weisman DS, Heine WF, Ciccone DN, O’Neill TB, Crick KE, Pierce KA, Lane WS, Rathbun G, Livingston DM, Weaver DT (2000) ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405:477–482

    Article  CAS  PubMed  Google Scholar 

  • Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH, Levine AJ (2000a) Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev 14:981–993

    Article  CAS  PubMed  Google Scholar 

  • Zhao S, Weng YC, Yuan SS, Lin YT, Hsu HC, Lin SC, Gerbino E, Song MH, Zdzienicka MZ, Gatti RA, Shay JW, Ziv Y, Shiloh Y, Lee EY (2000b) Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405:473–477

    Article  CAS  PubMed  Google Scholar 

  • Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a research grant from the National Cancer Center. We thank members of the Lee laboratory for comments and help in this study.

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Authors and Affiliations

  1. National Cancer Center, 809 Madu-dong, Ilsan-gu, 411-764, Goyang, Gyeonggi, Korea

    Eun Ryoung Jang & Jong-Soo Lee

  2. College of Natural Sciences, Seoul National University, Seoul, Korea

    Eun Ryoung Jang

  3. Korea Advanced Institute of Science and Technology, Taejon, Korea

    Joo Hyen Lee & Dae-Sik Lim

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  1. Eun Ryoung Jang
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  2. Joo Hyen Lee
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  4. Jong-Soo Lee
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Correspondence to Jong-Soo Lee.

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Jang, E.R., Lee, J.H., Lim, DS. et al. Analysis of ataxia-telangiectasia mutated (ATM)- and Nijmegen breakage syndrome (NBS)-regulated gene expression patterns. J Cancer Res Clin Oncol 130, 225–234 (2004). https://doi.org/10.1007/s00432-003-0522-y

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  • DOI: https://doi.org/10.1007/s00432-003-0522-y

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