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:

CDC20, a potential cancer therapeutic target, is negatively regulated by p53

Oncogene volume 27, pages 1562–1571 (2008)Cite this article

Abstract

The p53 protein inhibits malignant transformation through direct and indirect regulation of transcription of many genes related to cell cycle, apoptosis and cellular senescence. A number of genes induced by p53 have been well characterized, but biological significance of genes whose expression was suppressed by p53 is still largely undisclosed. To clarify the roles of p53-suppressive genes in carcinogenesis, we analysed two data sets of whole-genome expression profiles, one for cells in which wild-type p53 was exogenously introduced and the other for a large number of clinical cancer tissues. Here, we identified CDC20 that was frequently upregulated in many types of malignancies and remarkably suppressed by ectopic introduction of p53. CDC20 expression was suppressed by genotoxic stresses in p53- and p21-dependent manners through CDE-CHR elements in the CDC20 promoter. Furthermore, small interference RNA (siRNA)-mediated silencing of p53 induced CDC20 expression in normal human dermal fibroblast cells. As we expected, treatment of cancer cells with siRNA against CDC20 induced G2/M arrest and suppressed cell growth. Our results indicate that p53 inhibits tumor cell growth through the indirect regulation of CDC20 and that CDC20 might be a good potential therapeutic target for a broad spectrum of human cancer.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  • Ashida S, Nakagawa H, Katagiri T, Furihata M, Iiizumi M, Anazawa Y et al. (2004). Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs. Cancer Res 64: 5963–5972.

    Article  CAS  PubMed  Google Scholar 

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282: 1497–1501.

    Article  CAS  PubMed  Google Scholar 

  • Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P et al. (2002). Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8: 282–288.

    Article  CAS  PubMed  Google Scholar 

  • el-Deiry WS . (1998). Regulation of p53 downstream genes. Semin Cancer Biol 8: 345–357.

    Article  CAS  PubMed  Google Scholar 

  • Fang G, Yu H, Kirschner MW . (1998). The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev 12: 1871–1883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fung TK, Poon RY . (2005). A roller coaster ride with the mitotic cyclins. Semin Cell Dev Biol 16: 335–342.

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa S, Furukawa Y, Li M, Satoh S, Kato T, Watanabe T et al. (2002). Genome-wide analysis of gene expression in intestinal-type gastric cancers using a complementary DNA microarray representing 23,040 genes. Cancer Res 62: 7012–7017.

    CAS  PubMed  Google Scholar 

  • Hirota E, Yan L, Tsunoda T, Ashida S, Fujime M, Shuin T et al. (2006). Genome-wide gene expression profiles of clear cell renal cell carcinoma: identification of molecular targets for treatment of renal cell carcinoma. Int J Oncol 29: 799–827.

    CAS  PubMed  Google Scholar 

  • Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M . (2002). Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem 277: 3247–3257.

    Article  CAS  PubMed  Google Scholar 

  • Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T et al. (1994). Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res 22: 3551–3555.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Innocente SA, Lee JM . (2005). p53 is a NF-Y- and p21-independent, Sp1-dependent repressor of cyclin B1 transcription. FEBS Lett 579: 1001–1007.

    Article  CAS  PubMed  Google Scholar 

  • Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M et al. (2004). Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10: 1321–1328.

    Article  CAS  PubMed  Google Scholar 

  • Jinawath N, Furukawa Y, Hasegawa S, Li M, Tsunoda T, Satoh S et al. (2004). Comparison of gene-expression profiles between diffuse- and intestinal-type gastric cancers using a genome-wide cDNA microarray. Oncogene 23: 6830–6844.

    Article  CAS  PubMed  Google Scholar 

  • Kaneta Y, Kagami Y, Katagiri T, Tsunoda T, Jin-nai I, Taguchi H et al. (2002). Prediction of sensitivity to STI571 among chronic myeloid leukemia patients by genome-wide cDNA microarray analysis. Jpn J Cancer Res 93: 849–856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kikuchi T, Daigo Y, Katagiri T, Tsunoda T, Okada K, Kakiuchi S et al. (2003). Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene 22: 2192–2205.

    Article  CAS  PubMed  Google Scholar 

  • Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH et al. (2005). Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells. Clin Cancer Res 11: 473–482.

    PubMed  Google Scholar 

  • Kitahara O, Furukawa Y, Tanaka T, Kihara C, Ono K, Yanagawa R et al. (2001). Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia. Cancer Res 61: 3544–3549.

    CAS  PubMed  Google Scholar 

  • Kitahara O, Katagiri T, Tsunoda T, Harima Y, Nakamura Y . (2002). Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis. Neoplasia 4: 295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maity SN, Sinha S, Ruteshouser EC, de Crombrugghe B . (1992). Three different polypeptides are necessary for DNA binding of the mammalian heteromeric CCAAT binding factor. J Biol Chem 267: 16574–16580.

    CAS  PubMed  Google Scholar 

  • Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y, Arakawa H . (2002). p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Res 62: 2883–2889.

    CAS  PubMed  Google Scholar 

  • Mondal G, Sengupta S, Panda CK, Gollin SM, Saunders WS, Roychoudhury S . (2007). Overexpression of Cdc20 leads to impairment of the spindle assembly checkpoint and aneuploidization in oral cancer. Carcinogenesis 28: 81–92.

    Article  CAS  PubMed  Google Scholar 

  • Nagayama S, Katagiri T, Tsunoda T, Hosaka T, Nakashima Y, Araki N et al. (2002). Genome-wide analysis of gene expression in synovial sarcomas using a cDNA microarray. Cancer Res 62: 5859–5866.

    CAS  PubMed  Google Scholar 

  • Nakamura T, Furukawa Y, Nakagawa H, Tsunoda T, Ohigashi H, Murata K et al. (2004). Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene 23: 2385–2400.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura Y . (2004). Isolation of p53-target genes and their functional analysis. Cancer Sci 95: 7–11.

    Article  CAS  PubMed  Google Scholar 

  • Nishidate T, Katagiri T, Lin ML, Mano Y, Miki Y, Kasumi F et al. (2004). Genome-wide gene-expression profiles of breast-cancer cells purified with laser microbeam microdissection: identification of genes associated with progression and metastasis. Int J Oncol 25: 797–819.

    CAS  PubMed  Google Scholar 

  • Obama K, Ura K, Li M, Katagiri T, Tsunoda T, Nomura A et al. (2005). Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma. Hepatology 41: 1339–1348.

    Article  CAS  PubMed  Google Scholar 

  • Ochi K, Daigo Y, Katagiri T, Nagayama S, Tsunoda T, Myoui A et al. (2004). Prediction of response to neoadjuvant chemotherapy for osteosarcoma by gene-expression profiles. Int J Oncol 24: 647–655.

    CAS  PubMed  Google Scholar 

  • Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T et al. (2000). p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102: 849–862.

    Article  CAS  PubMed  Google Scholar 

  • Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y et al. (2001). Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 61: 2129–2137.

    CAS  PubMed  Google Scholar 

  • Okada K, Katagiri T, Tsunoda T, Mizutani Y, Suzuki Y, Kamada M et al. (2003). Analysis of gene-expression profiles in testicular seminomas using a genome-wide cDNA microarray. Int J Oncol 23: 1615–1635.

    CAS  PubMed  Google Scholar 

  • Okutsu J, Tsunoda T, Kaneta Y, Katagiri T, Kitahara O, Zembutsu H et al. (2002). Prediction of chemosensitivity for patients with acute myeloid leukemia, according to expression levels of 28 genes selected by genome-wide complementary DNA microarray analysis. Mol Cancer Ther 1: 1035–1042.

    CAS  PubMed  Google Scholar 

  • Ono K, Tanaka T, Tsunoda T, Kitahara O, Kihara C, Okamoto A et al. (2000). Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Cancer Res 60: 5007–5011.

    CAS  PubMed  Google Scholar 

  • Roth JA . (2006). Adenovirus p53 gene therapy. Expert Opin Biol Ther 6: 55–61.

    Article  CAS  PubMed  Google Scholar 

  • Seto E, Usheva A, Zambetti GP, Momand J, Horikoshi N, Weinmann R et al. (1992). Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc Natl Acad Sci USA 89: 12028–12032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712.

    Article  CAS  PubMed  Google Scholar 

  • Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783–792.

    Article  CAS  PubMed  Google Scholar 

  • Soussi T, Asselain B, Hamroun D, Kato S, Ishioka C, Claustres M et al. (2006). Meta-analysis of the p53 mutation database for mutant p53 biological activity reveals a methodologic bias in mutation detection. Clin Cancer Res 12: 62–69.

    Article  CAS  PubMed  Google Scholar 

  • St Clair S, Giono L, Varmeh-Ziaie S, Resnick-Silverman L, Liu WJ, Padi A et al. (2004). DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter. Mol Cell 16: 725–736.

    Article  PubMed  Google Scholar 

  • Sun Y . (2006). p53 and its downstream proteins as molecular targets of cancer. Mol Carcinog 45: 409–415.

    Article  CAS  PubMed  Google Scholar 

  • Takata R, Katagiri T, Kanehira M, Tsunoda T, Shuin T, Miki T et al. (2005). Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling. Clin Cancer Res 11: 2625–2636.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K et al. (2000). A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404: 42–49.

    Article  CAS  PubMed  Google Scholar 

  • Tanikawa C, Matsuda K, Fukuda S, Nakamura Y, Arakawa H . (2003). p53RDL1 regulates p53-dependent apoptosis. Nat Cell Biol 5: 216–223.

    Article  CAS  PubMed  Google Scholar 

  • Taniwaki M, Daigo Y, Ishikawa N, Takano A, Tsunoda T, Yasui W et al. (2006). Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer. Int J Oncol 29: 567–575.

    CAS  PubMed  Google Scholar 

  • Taylor WR, Schonthal AH, Galante J, Stark GR . (2001). p130/E2F4 binds to and represses the cdc2 promoter in response to p53. J Biol Chem 276: 1998–2006.

    Article  CAS  PubMed  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ . (2000). Surfing the p53 network. Nature 408: 307–310.

    Article  CAS  PubMed  Google Scholar 

  • Wells J, Boyd KE, Fry CJ, Bartley SM, Farnham PJ . (2000). Target gene specificity of E2F and pocket protein family members in living cells. Mol Cell Biol 20: 5797–5807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamabuki T, Daigo Y, Kato T, Hayama S, Tsunoda T, Miyamoto M et al. (2006). Genome-wide gene expression profile analysis of esophageal squamous cell carcinomas. Int J Oncol 28: 1375–1384.

    CAS  PubMed  Google Scholar 

  • Zaffaroni N, Pennati M, Daidone MG . (2005). Survivin as a target for new anticancer interventions. J Cell Mol Med 9: 360–372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Yeager AM, Smith SD, Findley HW . (1995). Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene. Blood 85: 1608–1614.

    CAS  PubMed  Google Scholar 

  • Zwicker J, Lucibello FC, Wolfraim LA, Gross C, Truss M, Engeland K et al. (1995). Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. EMBO J 14: 4514–4522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Akiko Takahashi for her technical assistance and Kazuhito Morioka for helpful discussion. This work was partly supported by grant no. 18687012 (K Matsuda) from Japan Society for the Promotion of Science and Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    T Kidokoro, C Tanikawa, T Katagiri, Y Nakamura & K Matsuda

  2. Promotion of Genome-Based Medicine Project, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Y Furukawa

Authors
  1. T Kidokoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Tanikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Katagiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Matsuda.

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

Kidokoro, T., Tanikawa, C., Furukawa, Y. et al. CDC20, a potential cancer therapeutic target, is negatively regulated by p53. Oncogene 27, 1562–1571 (2008). https://doi.org/10.1038/sj.onc.1210799

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210799

Keywords

This article is cited by

Search

Advanced search

Quick links