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.

  • Short Report
  • Published:

The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library

Oncogene volume 24, pages 6976–6981 (2005)Cite this article

Abstract

Tumor suppressor p53 forms a homo-tetramer through its COOH-terminal oligomerization domain and acts as a sequence-specific transcription factor. We have analysed the interrelation among the transcriptional activities, the structure and the cancer-related mutations in the oligomerization domain by using a comprehensive missense mutation library. Here, we examined the ability of 184 mutant p53s in the domain to form an oligomer by expressing these mutant p53s in yeast, and compared the data with the previous information. We showed that specific residues in the α-helix and the β-strand of the oligomerization domain were critical for both oligomer formation and sequence-specific transactivation, and the activities were closely related. In particular, the α-helix was more sensitive to amino-acid substitutions than the β-strand. We found identity in the interrelation between the two activities, that is, monomer mutants were transcriptionally inactive whereas dimer and tetramer mutants retained their transcriptional activities. In TP53 mutation databases, a small number of mutations have been reported in this domain. Surprisingly, most do not encode p53s defective in functional properties. These results indicate that, although oligomer formation is essential for p53 transactivation function, the inactivation of oligomer formation and therefore the inactivation of transactivation may not be essential for tumor suppression by p53 because they do not lead to oncogenic proteins.

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

Similar content being viewed by others

References

  • Ashcroft M, Kubbutat MH and Vousden KH . (1999). Mol. Cell. Biol., 19, 1751–1758.

  • Barlev NA, Liu L, Chehab NH, Mansfield K, Harris KG, Halazonetis TD and Berger SL . (2001). Mol. Cell, 8, 1243–1254.

  • Brachmann RK, Vidal M and Boeke JD . (1996). Proc. Natl. Acad. Sci. USA, 93, 4091–4095.

  • Chene P and Bechter E . (1999). J. Mol. Biol., 288, 891–897.

  • Chene P, Mittl P and Grutter M . (1997). J. Mol. Biol., 273, 873–881.

  • Clore GM, Omichinski JG, Sakaguchi K, Zambrano N, Sakamoto H, Appella E and Gronenborn AM . (1995). Science, 267, 1515–1516.

  • Davison TS, Yin P, Nie E, Kay C and Arrowsmith CH . (1998). Oncogene, 17, 651–656.

  • DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, Zambetti G and Kriwacki RW . (2002). Nat. Struct. Biol., 9, 12–16.

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B . (1993). Cell, 75, 817–825.

  • Halazonetis TD and Kandil AN . (1993). EMBO J., 12, 5057–5064.

  • Ishioka C, Englert C, Winge P, Yan YX, Engelstein M and Friend SH . (1995). Oncogene, 10, 1485–1492.

  • Ishioka C, Shimodaira H, Englert C, Shimada A, Osada M, Jia LQ, Suzuki T, Gamo M and Kanamaru R . (1997). Biochem. Biophys. Res. Commun., 232, 54–60.

  • Jeffrey PD, Gorina S and Pavletich NP . (1995). Science, 267, 1498–1502.

  • Kakudo Y, Shibata H, Otsuka K, Kato S and Ishioka C . (2005). Cancer Res., 65, 2108–2114.

  • Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R and Ishioka C . (2003). Proc. Natl. Acad. Sci. USA, 100, 8424–8429.

  • Lee W, Harvey TS, Yin Y, Yau P, Litchfield D and Arrowsmith CH . (1994). Nat. Struct. Biol., 1, 877–890.

  • Lomax ME, Barnes DM, Hupp TR, Picksley SM and Camplejohn RS . (1998). Oncogene, 17, 643–649.

  • Marchenko ND, Zaika A and Moll UM . (2000). J. Biol. Chem., 275, 16202–16212.

  • Mateu MG and Fersht AR . (1998). EMBO J., 17, 2748–2758.

  • Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P and Moll UM . (2003). Mol. Cell, 11, 577–590.

  • Miller M, Lubkowski J, Rao JK, Danishefsky AT, Omichinski JG, Sakaguchi K, Sakamoto H, Appella E, Gronenborn AM and Clore GM . (1996). FEBS Lett., 399, 166–170.

  • Mittl PR, Chene P and Grutter MG . (1998). Acta Crystallogr D Biol. Crystallogr., 54, 86–89.

  • Miyashita T and Reed JC . (1995). Cell, 80, 293–299.

  • Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T and Tanaka N . (2000). Science, 288, 1053–1058.

  • Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW, Kruzel E and Radinsky R . (1995). Mol. Cell. Biol., 15, 3032–3040.

  • Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B . (1997). Nature, 389, 300–305.

  • Roth J, Dobbelstein M, Freedman DA, Shenk T and Levine AJ . (1998). EMBO J., 17, 554–564.

  • Sakaguchi K, Herrera JE, Saito S, Miki T, Bustin M, Vassilev A, Anderson CW and Appella E . (1998). Genes Dev., 12, 2831–2841.

  • Shaulian E, Zauberman A, Ginsberg D and Oren M . (1992). Mol. Cell. Biol., 12, 5581–5592.

  • Shaulian E, Zauberman A, Milner J, Davies EA and Oren M . (1993). EMBO J., 12, 2789–2797.

  • Slingerland JM and Benchimol S . (1991). J. Cell. Physiol., 148, 391–395.

  • Soussi T, Kato S, Levy PP and Ishioka C . (2005). Hum. Mutat., 25, 6–17.

  • Srivastava S, Wang S, Tong YA, Pirollo K and Chang EH . (1993). Oncogene, 8, 2449–2456.

  • Stommel JM, Marchenko ND, Jimenez GS, Moll UM, Hope TJ and Wahl GM . (1999). EMBO J., 18, 1660–1672.

  • Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, Takei Y and Nakamura Y . (2000). Nature, 404, 42–49.

  • Tao W and Levine AJ . (1999). Proc. Natl. Acad. Sci. USA, 96, 6937–6941.

  • Unger T, Mietz JA, Scheffner M, Yee CL and Howley PM . (1993). Mol. Cell. Biol., 13, 5186–5194.

  • Unger T, Nau MM, Segal S and Minna JD . (1992). EMBO J., 11, 1383–1390.

  • Varley JM, McGown G, Thorncroft M, Cochrane S, Morrison P, Woll P, Kelsey AM, Mitchell EL, Boyle J, Birch JM and Evans DG . (1996). Oncogene, 12, 2437–2442.

  • Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S, Ronai Z, Blandino G, Schneider C and Del Sal G . (2002). Nature, 419, 853–857.

  • Zheng H, You H, Zhou XZ, Murray SA, Uchida T, Wulf G, Gu L, Tang X, Lu KP and Xiao ZX . (2002). Nature, 419, 849–853.

Download references

Acknowledgements

We thank Shuang-Yin Han and Wen Liu for their contribution to the construction of the p53 mutation library. We also thank Yuka Fujimaki for technical assistance. This study was supported in part by grants-in-aid from the Ministry of Education and Science, Sports and Culture (to CI and SK) and the Gonryo Medical Foundation (CI).

Author information

Author notes

  1. Tomohiro Kawaguchi and Shunsuke Kato: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Clinical Oncology, Institute of Development, Aging and Cancer (IDAC), and Tohoku University Hospital, Tohoku University, Sendai, 980-8575, Japan

    Tomohiro Kawaguchi, Shunsuke Kato, Kazunori Otsuka, Gou Watanabe & Chikashi Ishioka

  2. Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, 890-8574, Japan

    Tomohiro Kawaguchi, Toshihiro Kumabe, Teiji Tominaga & Takashi Yoshimoto

Authors
  1. Tomohiro Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shunsuke Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazunori Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gou Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshihiro Kumabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Teiji Tominaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takashi Yoshimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chikashi Ishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chikashi Ishioka.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawaguchi, T., Kato, S., Otsuka, K. et al. The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. Oncogene 24, 6976–6981 (2005). https://doi.org/10.1038/sj.onc.1208839

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208839

Keywords

This article is cited by

Search

Advanced search

Quick links