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:

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

Oncogene volume 26, pages 509–520 (2007)Cite this article

Abstract

As alterations in retinoblastoma (RB)/E2F pathway are commonly found in human cancers, the molecular mechanism underlying cell cycle deregulation caused by the mutations in the RB/E2F pathway needs to be investigated extensively. Compared with good understanding of RB/E2F functions in G1–S cell cycle progression, it is not fully understood how an abrogated RB pathway affects the G2–M phase of the cell cycle. Here, we report that disruption of RB accelerated G2–M progression in the presence of DNA damage by elevating the expression of a set of mitotic regulatory genes. We generated RB(+)- and (−)-matched cells using short hairpin RNA. In the RB(−) cells, the G2/M checkpoint mediated by a DNA-damaging agent was over-ridden. With microarray analysis, we found that the expression of key G2–M regulatory genes was upregulated in RB(−) cells. In particular, we demonstrated that the proto-oncogene ECT2 was directly regulated by E2Fs. Furthermore, suppression of ECT2 expression by small interfering RNA in RB(−) cells resulted in cytokinesis arrest, suggesting that RB(−) cells lack the regulation of E2F-mediated cytokinesis. These results indicate that aberrant ECT2 expression, observed in various human tumors, could be the direct result of RB/E2F pathway deficiency, thereby contributing to cell division in cancers.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Black EP, Huang E, Dressman H, Rempel R, Laakso N, Asa SL et al. (2003). Cancer Res 63: 3716–3723.

  • Blangy A, Lane HA, d’Herin P, Harper M, Kress M, Nigg EA . (1995). Cell 83: 1159–1169.

  • Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA . (1999). Proc Natl Acad Sci USA 96: 1002–1007.

  • Cam H, Dynlacht BD . (2003). Cancer Cell 3: 311–316.

  • Clemens F, Verma R, Ramnath J, Landolph JR . (2005). Toxicol Appl Pharmacol 206: 138–149.

  • Drechsel DN, Hyman AA, Hall A, Glotzer M . (1997). Curr Biol 7: 12–23.

  • Dyson N . (1998). Genes Dev 12: 2245–2262.

  • Flatt PM, Tang LJ, Scatena CD, Szak ST, Pietenpol JA . (2000). Mol Cell Biol 20: 4210–4223.

  • Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM et al. (1986). Nature 323: 643–646.

  • Fung YK, Murphree AL, T’Ang A, Qian J, Hinrichs SH, Benedict WF . (1987). Science 236: 1657–1661.

  • Gassmann R, Carvalho A, Henzing AJ, Ruchaud S, Hudson DF, Honda R et al. (2004). J Cell Biol 166: 179–191.

  • Hateboer G, Wobst A, Petersen BO, Le Cam L, Vigo E, Sardet C et al. (1998). Mol Cell Biol 18: 6679–6697.

  • Hernando E, Nahle Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M et al. (2004). Nature 430: 797–802.

  • Hill E, Clarke M, Barr FA . (2000). EMBO J 19: 5711–5719.

  • Ishida S, Huang E, Zuzan H, Spang R, Leone G, West M et al. (2001). Mol Cell Biol 21: 4684–4699.

  • Jiang Y, Saavedra HI, Holloway MP, Leone G, Altura RA . (2004). J Biol Chem 279: 40511–40520.

  • Johnson DG, Schwarz JK, Cress WD, Nevins JR . (1993). Nature 365: 349–352.

  • Kimura K, Cuvier O, Hirano T . (2001). J Biol Chem 276: 5417–5420.

  • Kimura K, Tsuji T, Takada Y, Miki T, Narumiya S . (2000). J Biol Chem 275: 17233–17236.

  • Mayhew CN, Bosco EE, Fox SR, Okaya T, Tarapore P, Schwemberger SJ et al. (2005). Cancer Res 65: 4568–4577.

  • Miki T, Smith CL, Long JE, Eva A, Fleming TP . (1993). Nature 362: 462–465.

  • Muller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassilli E et al. (2001). Genes Dev 15: 267–285.

  • Namba R, Maglione JE, Young LJ, Borowsky AD, Cardiff RD, MacLeod CL et al. (2004). Mol Cancer Res 2: 453–463.

  • Polager S, Ginsberg D . (2003). J Biol Chem 278: 1443–1449.

  • Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA et al. (2002). Genes Dev 16: 245–256.

  • Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T . (2003). Nature 424: 223–228.

  • Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B et al. (2000). Genes Dev 14: 3037–3050.

  • Sahai E, Marshall CJ . (2002). Nat Rev Cancer 2: 133–142.

  • Saito S, Liu XF, Kamijo K, Raziuddin R, Tatsumoto T, Okamoto I et al. (2004). J Biol Chem 279: 7169–7179.

  • Saito S, Tatsumoto T, Lorenzi MV, Chedid M, Kapoor V, Sakata H et al. (2003). J Cell Biochem 90: 819–836.

  • Sakata H, Rubin JS, Taylor WG, Miki T . (2000). Hepatology 32: 193–199.

  • Schulze A, Zerfass K, Spitkovsky D, Henglein B, Jansen-Durr P . (1994). Oncogene 9: 3475–3482.

  • Sherr CJ . (2000). Cancer Res 60: 3689–3695.

  • Sherr CJ, McCormick F . (2002). Cancer Cell 2: 103–112.

  • Sherr CJ, Roberts JM . (1999). Genes Dev 13: 1501–1512.

  • Tatsumoto T, Xie X, Blumenthal R, Okamoto I, Miki T . (1999). J Cell Biol 147: 921–928.

  • Wang JY, Naderi S, Chen TT . (2001). Acta Oncol 40: 689–695.

  • Weinberg RA . (1995). Cell 81: 323–330.

  • Westwick JK, Lee RJ, Lambert QT, Symons M, Pestell RG, Der CJ et al. (1998). J Biol Chem 273: 16739–16747.

  • Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR et al. (1998). Proc Natl Acad Sci USA 95: 3603–3608.

  • Yen CC, Chen YJ, Pan CC, Lu KH, Chen PC, Hsia JY et al. (2005). World J Gastroenterol 11: 1267–1272.

  • Young AP, Nagarajan R, Longmore GD . (2003). Oncogene 22: 7209–7217.

Download references

Author information

Authors and Affiliations

  1. Functional Genomics, Banyu Tsukuba Research Institute, Merck Research Laboratory, Tsukuba, Ibaraki, Japan

    T Eguchi, T Takaki, H Itadani & H Kotani

Authors
  1. T Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Takaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Itadani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Kotani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Kotani.

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

Eguchi, T., Takaki, T., Itadani, H. et al. RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene. Oncogene 26, 509–520 (2007). https://doi.org/10.1038/sj.onc.1209810

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209810

Keywords

This article is cited by

Search

Advanced search

Quick links