Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression

Oncogene volume 27, pages 2187–2197 (2008)Cite this article

Abstract

Inverted CCAAT box-binding protein of 90 kDa (ICBP90) is over-expressed in several types of cancer, including breast, prostate and lung cancers. In search for proteins that interact with the set and ring-associated (SRA) domain of ICBP90, we used the two-hybrid system and screened a placental cDNA library. Several clones coding for a new domain of DNMT1 were found. The interaction, between the ICBP90 SRA domain and the DNMT1 domain, has been confirmed with purified proteins by glutathione-S-transferase pull-down experiments. We checked whether ICBP90 and DNMT1 are present in the same macro-molecular complexes in Jurkat cells and immortalized human vascular smooth muscle cells (HVTs-SM1). Co-immunoprecipitation experiments showed that ICBP90 and DNMT1 are present in the same molecular complex, which was further confirmed by co-localization experiments as assessed by immunocytochemistry. Downregulation of ICBP90 and DNMT1 decreased VEGF gene expression, a major pro-angiogenic factor, whereas those of p16INK4A gene and RB1 gene were significantly enhanced. Together, these results indicate that DNMT1 and ICBP90 are involved in VEGF gene expression, possibly via an interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 and an upregulation of p16INK4A. They further suggest a new role of ICBP90 in the relationship between histone ubiquitination and DNA methylation in the context of tumoral angiogenesis and tumour suppressor genes silencing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Arima Y, Hirota T, Bronner C, Mousli M, Fujiwara T, Niwa S et al. (2004). Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition. Genes Cells 9: 131–142.

    Article  CAS  Google Scholar 

  • Bartel P, Chien CT, Sternglanz R, Fields S . (1993). Elimination of false positives that arise in using the two-hybrid system. Biotechniques 14: 920–924.

    CAS  PubMed  Google Scholar 

  • Baumbusch LO, Thorstensen T, Krauss V, Fischer A, Naumann K, Assalkhou R et al. (2001). The Arabidopsis thaliana genome contains at least 29 active genes encoding SET domain proteins that can be assigned to four evolutionarily conserved classes. Nucleic Acids Res 29: 4319–4333.

    Article  CAS  Google Scholar 

  • Bonapace IM, Latella L, Papait R, Nicassio F, Sacco A, Muto M et al. (2002). Np95 is regulated by E1A during mitotic reactivation of terminally differentiated cells and is essential for S phase entry. J Cell Biol 157: 909–914.

    Article  CAS  Google Scholar 

  • Bostick M, Kim JK, Estève PO, Clark A, Pradhan S, Jacobsen SE . (2007). UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317: 1760–1764.

    Article  CAS  Google Scholar 

  • Bronner C, Achour M, Arima Y, Chataigneau T, Saya H, Schini-Kerth VB . (2007). The UHRF family: oncogenes that are drugable targets for cancer therapy in the near future? Pharmacol Ther 115: 419–434.

    Article  CAS  Google Scholar 

  • Caracciolo V, Reiss K, Khalili K, De Falco G, Giordano A . (2006). Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus. Oncogene 25: 5294–5301.

    Article  CAS  Google Scholar 

  • Chen DR, Wang PL, Huang AL, Zhang BQ . (2006). Effects of dnmt1 gene silencing on cell cycle, proliferation, and apoptosis of gastric cancer cell line AGS. Ai Zheng 25: 308–314.

    CAS  PubMed  Google Scholar 

  • Cheng CH, Kuchta RD . (1993). DNA polymerase epsilon: aphidicolin inhibition and the relationship between polymerase and exonuclease activity. Biochemistry 32: 8568–8574.

    Article  CAS  Google Scholar 

  • Chuang JL, Davie JR, Wynn RM, Chuang DT . (2000). Production of recombinant mammalian holo-E2 and E3 and reconstitution of functional branched-chain alpha-keto acid dehydrogenase complex with recombinant E1. Methods Enzymol 324: 192–200.

    Article  CAS  Google Scholar 

  • Citterio E, Papait R, Nicassio F, Vecchi M, Gomiero P, Mantovani R et al. (2004). Np95 is a histone-binding protein endowed with ubiquitin ligase activity. Mol Cell Biol 24: 2526–2535.

    Article  CAS  Google Scholar 

  • Crnogorac-Jurcevic T, Gangeswaran R, Bhakta V, Capurso G, Lattimore S, Akada M et al. (2005). Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma. Gastroenterology 129: 1454–1463.

    Article  CAS  Google Scholar 

  • Espada J, Ballestar E, Fraga MF, Villar-Garea A, Juarranz A, Stockert JC et al. (2004). Human DNA methyltransferase 1 is required for maintenance of the histone H3 modification pattern. J Biol Chem 279: 37175–37184.

    Article  CAS  Google Scholar 

  • Fournel M, Sapieha P, Beaulieu N, Besterman JM, MacLeod AR . (1999). Down-regulation of human DNA-(cytosine-5) methyltransferase induces cell cycle regulators p16(ink4A) and p21(WAF/Cip1) by distinct mechanisms. J Biol Chem 274: 24250–24256.

    Article  CAS  Google Scholar 

  • Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T . (2000). DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24: 88–91.

    Article  CAS  Google Scholar 

  • Gabellini C, Del Bufalo D, Zupi G . (2006). Involvement of RB gene family in tumor angiogenesis. Oncogene 25: 5326–5332.

    Article  CAS  Google Scholar 

  • Giacinti C, Giordano A . (2006). RB and cell cycle progression. Oncogene 25: 5220–5227.

    Article  CAS  Google Scholar 

  • Hopfner R, Mousli M, Jeltsch JM, Voulgaris A, Lutz Y, Marin C et al. (2000). ICBP90, a novel human CCAAT binding protein, involved in the regulation of topoisomerase IIα expression. Cancer Res 60: 121–128.

    CAS  PubMed  Google Scholar 

  • Hopfner R, Mousli M, Oudet P, Bronner C . (2002). Overexpression of ICBP90, a novel CCAAT-binding protein, overcomes cell contact inhibition by forcing topoisomerase IIα expression. Anticancer Res 22: 3165–3170.

    CAS  PubMed  Google Scholar 

  • Hsieh JK, Kletsas D, Clunn G, Hughes AD, Schachter M, Mason CM . (2000). p53, p21(WAF1/CIP1), and MDM2 involvement in the proliferation and apoptosis in an in vitro model of conditionally immortalized human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20: 973–981.

    Article  CAS  Google Scholar 

  • Ingham RJ, Gish G, Pawson T . (2004). The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture. Oncogene 23: 1972–1984.

    Article  CAS  Google Scholar 

  • Jeanblanc M, Mousli M, Hopfner R, Bathami K, Martinet N, Abbady AQ et al. (2005). The retinoblastoma gene and its product are targeted by ICBP90: a key mechanism in the G1/S transition during the cell cycle. Oncogene 24: 7337–7345.

    Article  CAS  Google Scholar 

  • Jenkins Y, Markovtsov V, Lang W, Sharma P, Pearsall D, Warner J et al. (2005). Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mol Biol Cell 16: 5621–5629.

    Article  CAS  Google Scholar 

  • Kimura H, Nakamura T, Ogawa T, Tanaka S, Shiota K . (2003). Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways. Nucleic Acids Res 31: 3101–3113.

    Article  CAS  Google Scholar 

  • Leonhardt H, Page AW, Weier HU, Bestor TH . (1992). A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71: 865–873.

    Article  CAS  Google Scholar 

  • Levine AJ . (1997). p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.

    Article  CAS  Google Scholar 

  • Lorenzato M, Caudroy S, Bronner C, Evrard G, Simon M, Durlach A et al. (2005). Cell cycle and/or proliferation markers: what is the best method to discriminate cervical high-grade lesions? Hum Pathol 36: 1101–1107.

    Article  CAS  Google Scholar 

  • Macaluso M, Cinti C, Russo G, Russo A, Giordano A . (2003). pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of estrogen receptor-alpha in breast cancer. Oncogene 22: 3511–3517.

    Article  CAS  Google Scholar 

  • Macaluso M, Montanari M, Noto PB, Gregorio V, Bronner C, Giordano A . (2007). Epigenetic modulation of estrogen receptor-{alpha} by pRb family proteins: a novel mechanism in breast cancer. Cancer Res 67: 7731–7737.

    Article  CAS  Google Scholar 

  • McCabe MT, Davis JN, Day ML . (2005). Regulation of DNA methyltransferase 1 by the pRb/E2F1 pathway. Cancer Res 65: 3624–3632.

    Article  CAS  Google Scholar 

  • Miki K, Shimizu E, Yano S, Tani K, Sone S . (2001). Demethylation by 5-aza-2′-deoxycytidine (5-azadC) of p16INK4A gene results in downregulation of vascular endothelial growth factor expression in human lung cancer cell lines. Oncol Res 12: 335–342.

    Article  CAS  Google Scholar 

  • Milutinovic S, Zhuang Q, Niveleau A, Szyf M . (2003). Epigenomic stress response. Knockdown of DNA methyltransferase 1 triggers an intra-S-phase arrest of DNA replication and induction of stress response genes. J Biol Chem 278: 14985–14995.

    Article  CAS  Google Scholar 

  • Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H . (2005). Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci USA 102: 8905–8909.

    Article  CAS  Google Scholar 

  • Mousli M, Hopfner R, Abbady AQ, Monte D, Jeanblanc M, Oudet P et al. (2003). ICBP90 belongs to a new family of proteins with an expression that is deregulated in cancer cells. Br J Cancer 89: 120–127.

    Article  CAS  Google Scholar 

  • Mukhopadhyay D, Tsiokas L, Sukhatme VP . (1995). Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res 55: 6161–6165.

    CAS  PubMed  Google Scholar 

  • Naumann K, Fischer A, Hofmann I, Krauss V, Phalke S, Irmler K et al. (2005). Pivotal role of AtSUVH2 in heterochromatic histone methylation and gene silencing in Arabidopsis. EMBO J 24: 1418–1429.

    Article  CAS  Google Scholar 

  • Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, O'Carroll D et al. (2001). Rb targets histone H3 methylation and HP1 to promoters. Nature 412: 561–565.

    Article  CAS  Google Scholar 

  • Oak MH, El Bedoui J, Schini-Kerth VB . (2005). Antiangiogenic properties of natural polyphenols from red wine and green tea. J Nutr Biochem 16: 1–8.

    Article  CAS  Google Scholar 

  • Oba-Shinjo SM, Bengtson MH, Winnischofer SM, Colin C, Vedoy CG, de Mendonca Z et al. (2005). Identification of novel differentially expressed genes in human astrocytomas by cDNA representational difference analysis. Brain Res Mol Brain Res 140: 25–33.

    Article  CAS  Google Scholar 

  • Ohta T, Fukuda M . (2004). Ubiquitin and breast cancer. Oncogene 23: 2079–2088.

    Article  CAS  Google Scholar 

  • Papait R, Pistore C, Negri D, Pecoraro D, Cantarini L, Bonapace IM . (2007). Np95 is implicated in pericentromeric heterochromatin replication and in major satellite silencing. Mol Biol Cell 18: 1098–1106.

    Article  CAS  Google Scholar 

  • Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S et al. (2006). DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27: 1160–1168.

    Article  CAS  Google Scholar 

  • Rain JC, Selig L, De Reuse H, Battaglia V, Reverdy C, Simon S et al. (2001). The protein-protein interaction map of Helicobacter pylori. Nature 409: 211–215.

    Article  CAS  Google Scholar 

  • Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP . (2000). DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25: 338–342.

    Article  CAS  Google Scholar 

  • Salimath B, Marmé D, Finkenzeller G . (2000). Expression of the vascular endothelial growth factor gene is inhibited by p73. Oncogene 19: 3470–3476.

    Article  CAS  Google Scholar 

  • Schaaf GJ, Ruijter JM, van Ruissen F, Zwijnenburg DA, Waaijer R, Valentijn LJ et al. (2005). Full transcriptome analysis of rhabdomyosarcoma, normal, and fetal skeletal muscle: statistical comparison of multiple SAGE libraries. FASEB J 19: 404–406.

    Article  CAS  Google Scholar 

  • Suzuki M, Sunaga N, Shames DS, Toyooka S, Gazdar AF, Minna JD . (2004). RNA interference-mediated knockdown of DNA methyltransferase 1 leads to promoter demethylation and gene re-expression in human lung and breast cancer cells. Cancer Res 64: 3137–3143.

    Article  CAS  Google Scholar 

  • Turek-Plewa J, Jagodzinski PP . (2005). The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett 10: 631–647.

    CAS  PubMed  Google Scholar 

  • Uemura T, Kubo E, Kanari Y, Ikemura T, Tatsumi K, Muto M . (2000). Temporal and spatial localization of novel nuclear protein NP95 in mitotic and meiotic cells. Cell Struct Funct 25: 149–159.

    Article  CAS  Google Scholar 

  • Unoki M, Nishidate T, Nakamura Y . (2004). ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 23: 7601–7610.

    Article  CAS  Google Scholar 

  • Vallbohmer D, Brabender J, Yang D, Schneider PM, Metzger R, Danenberg KD et al. (2006). DNA methyltransferases messenger RNA expression and aberrant methylation of CpG islands in non-small-cell lung cancer: association and prognostic value. Clin Lung Cancer 8: 39–44.

    Article  CAS  Google Scholar 

  • Vojtek AB, Hollenberg SM . (1995). Ras-Raf interaction: two-hybrid analysis. Methods Enzymol 255: 331–342.

    Article  CAS  Google Scholar 

  • Wang G, Miskimins R, Miskimins WK . (2000). Mimosine arrests cells in G1 by enhancing the levels of p27(Kip1). Exp Cell Res 254: 64–71.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study has been supported by grants of the Ligue contre le Cancer, Comité du Haut-Rhin, France. Mayada Achour is a fellowship from the Syrian Higher Education Ministry. Christian Bronner is Chargé de Recherches at the Institut National de la Santé et de la Recherche Médicale.

Author information

Authors and Affiliations

  1. Institut Gilbert-Laustriat, UMR 7175 CNRS/Université Louis Pasteur (Strasbourg I), Départment de Pharmacologie et Physicochimie, Faculté de Pharmacie, Illkirch, France

    M Achour, P Rondé, M Alhosin, C Charlot, T Chataigneau, M Jeanblanc, V B Schini-Kerth & C Bronner

  2. Hybrigenics, 3-5 impasse Reille, Paris, France

    X Jacq

  3. Sbarro Institute of Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA

    M Macaluso & A Giordano

  4. Department of Human Pathology and Oncology, University of Siena, Siena, Italy

    M Macaluso & A Giordano

  5. Clinical Pharmacology, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, St Mary's Hospital, London, UK

    A D Hughes

Authors
  1. M Achour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Jacq
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Rondé
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Alhosin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Charlot
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Chataigneau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Jeanblanc
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Macaluso
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A D Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. V B Schini-Kerth
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C Bronner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Bronner.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Achour, M., Jacq, X., Rondé, P. et al. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene 27, 2187–2197 (2008). https://doi.org/10.1038/sj.onc.1210855

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210855

Keywords

This article is cited by

Search

Advanced search

Quick links