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 Paper
  • Published:

Downregulation of β-catenin by p53 involves changes in the rate of β-catenin phosphorylation and Axin dynamics

Oncogene volume 23, pages 4444–4453 (2004)Cite this article

Abstract

β-Catenin, a structural component of cell–cell adhesions, is also a potent signaling molecule in the Wnt pathway activating target genes together with Lef/Tcf transcription factors. In colorectal and many other types of cancer, β-catenin is hyperactive owing to mutations in β-catenin, or in components regulating β-catenin degradation. Deregulated β-catenin can cause the activation of p53, a key tumor suppressor mutated in most cancers. Activated p53 can feed back and downregulate β-catenin. Here we investigated the mechanisms involved in downregulation of β-catenin by p53. We found that the p53-mediated reduction in β-catenin involves enhanced phosphorylation of β-catenin on key NH2-terminal serines and requires CK1 and GSK-3β activities, both being components of the β-catenin degradation machinery. Mutations in these NH2-terminal β-catenin serines blocked the ability of p53 to enhance the turnover of β-catenin. p53 also induced a shift in the distribution of the scaffold molecule Axin to a Triton X-100-soluble fraction, and led to depletion of β-catenin from this Triton-soluble fraction. The majority of Axin and phosphorylated β-catenin, however, colocalized in Triton X-100-insoluble punctate aggregates near the plasma membrane, and kinetics studies indicated that in the presence of p53 the movement of Axin into and out of the Triton X-100-insoluble fraction is accelerated. These results suggest that p53 induces a faster mobilization of Axin into the degradation complex thereby enhancing β-catenin turnover as part of a protective mechanism against the development of cancer.

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 7
Figure 6

Similar content being viewed by others

References

  • Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y and Alkalay I . (2002). Genes Dev., 16, 1066–1076.

  • Amson RB, Nemani M, Roperch JP, Israeli D, Bougueleret L, Le Gall I, Medhioub M, Linares-Cruz G, Lethrosne F, Pasturaud P, Piouffre L, Prieur S, Susini L, Alvaro V, Millasseau P, Guidicelli C, Bui H, Massart C, Cazes L, Dufour F, Bruzzoni-Giovanelli H, Owadi H, Hennion C, Charpak G, Dausset J, Calvo F, Oren M, Cohen D and Telerman A . (1996). Proc. Natl. Acad. Sci. USA, 93, 3953–3957.

  • Behrens J, von Kries J, Kuhl M, Bruhn L, Wedlich D, Grosschedl R and Birchmeier W . (1996). Nature, 382, 638–642.

  • Ben-Ze'ev A and Geiger B . (1998). Curr. Opin. Cell Biol., 10, 629–639.

  • Bienz M and Clevers H . (2000). Cell, 103, 311–320.

  • Brummelkamp TR, Bernards R and Agami R . (2002). Science, 296, 550–553.

  • Cadigan KM and Nusse R . (1997). Genes Dev., 11, 3286–3305.

  • Cliffe A, Hamada F and Bienz M . (2003). Curr. Biol., 13, 960–966.

  • Conacci-Sorrell ME, Ben-Yedidia T, Shtutman M, Feinstein E, Einat P and Ben-Ze'ev A . (2002). Genes Dev., 16, 2058–2072.

  • Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC and Pearl LH . (2003). EMBO J., 22, 494–501.

  • Damalas A, Ben-Ze'ev A, Simcha I, Shtutman M, Leal J, Zhurinsky J, Geiger B and Oren M . (1999). EMBO J., 18, 3054–3063.

  • Damalas A, Kahan S, Shtutman M, Ben-Ze'ev A and Oren M . (2001). EMBO J., 20, 4912–4922.

  • Hart M, Concordet J, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R and Polakis P . (1999). Curr. Biol., 9, 207–210.

  • Hart M, de los Santos R, Albert I, Rubinfeld B and Polakis P . (1998). Curr. Biol., 8, 573–581.

  • He T, Sparks A, Rago C, Hermeking H, Zawel L, da Costa L, Morin P, Vogelstein B and Kinzler K . (1998). Science, 281, 1509–1512.

  • Henderson BR . (2000). Nat. Cell Biol., 2, 653–660.

  • Hu G and Fearon ER . (1999). Mol. Cell. Biol., 19, 724–732.

  • Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann B and Kemler R . (1996). Mech. Dev., 59, 3–10.

  • Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S and Kikuchi A . (1998). EMBO J., 17, 1371–1384.

  • Kemler R . (1993). Trends Genet., 9, 317–321.

  • Kinzler KW and Vogelstein B . (1996). Cell, 87, 159–170.

  • Korinek V, Barker N, Morin P, van Wichen D, de Weger R, Kinzler K, Vogelstein B and Clevers H . (1997). Science, 275, 1784–1787.

  • Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X and He X . (2002). Cell, 108, 837–847.

  • Liu J, Stevens J, Rote C, Yost H, Hu Y, Neufeld K, White R and Matsunami N . (2001). Mol. Cell, 7, 927–936.

  • Matsuzawa S and Reed J . (2001). Mol. Cell, 7, 915–926.

  • Matsuzawa S, Takayama S, Froesch BA, Zapata JM and Reed JC . (1998). EMBO J., 17, 2736–2747.

  • Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O and Clevers H . (1996). Cell, 86, 391–399.

  • Morin P, Sparks A, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler K . (1997). Science, 275, 1787–1790.

  • Oren M . (2003). Cell Death Differ., 10, 431–442.

  • Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Maya R, Moas M, Seger R, Taya Y and Ben-Ze'ev A . (2002). Ann. NY Acad. Sci., 973, 374–383.

  • Peifer M and Polakis P . (2000). Science, 287, 1606–1609.

  • Persad S, Troussard AA, McPhee TR, Mulholland DJ and Dedhar S . (2001). J. Cell Biol., 153, 1161–1174.

  • Polakis P . (2000). Genes Dev., 14, 1837–1851.

  • Polakis P . (2002). Curr. Biol., 12, R499–R501.

  • Roperch JP, Lethrone F, Prieur S, Piouffre L, Israeli D, Tuynder M, Nemani M, Pasturaud P, Gendron MC, Dausset J, Oren M, Amson RB and Telerman A . (1999). Proc. Natl. Acad. Sci. USA, 96, 8070–8073.

  • Rosin-Arbesfeld R, Townsley F and Bienz M . (2000). Nature, 406, 1009–1012.

  • Sadot E, Geiger B, Oren M and Ben-Ze'ev A . (2001). Mol. Cell. Biol., 21, 6768–6781.

  • Sherr CJ and Weber JD . (2000). Curr. Opin. Genet. Dev., 10, 94–99.

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R and Ben-Ze'ev A . (1999). Proc. Natl. Acad. Sci. USA, 96, 5522–5527.

  • Simcha I, Shtutman M, Salomon D, Zhurinsky J, Sadot E, Geiger B and Ben-Ze'ev A . (1998). J. Cell Biol., 141, 1433–1448.

  • Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S and Mak TW . (2001). Mol. Cell, 8, 317–325.

  • Tetsu O and McCormick F . (1999). Nature, 398, 422–426.

  • Tolwinski NS, Wehrli M, Rives A, Erdeniz N, DiNardo S and Wieschaus E . (2003). Dev. Cell, 4, 407–418.

  • Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV and Jope RS . (2002). Proc. Natl. Acad. Sci. USA, 99, 7951–7955.

  • Willert K and Nusse R . (1998). Curr. Opin. Genet. Dev., 8, 95–102.

  • Winston J, Strack P, Beer-Romero P, Chu C, Elledge S and Harper J . (1999). Genes Dev., 13, 270–283.

  • Yanagawa S, Matsuda Y, Lee JS, Matsubayashi H, Sese S, Kadowaki T and Ishimoto A . (2002). EMBO J., 21, 1733–1742.

  • Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek T, Perry W, Lee J, Tilghman S, Gumbiner B and Costantini F . (1997). Cell, 90, 181–192.

Download references

Acknowledgements

We thank J Zhurinsky, B Geiger and M Shtutman for their continued interest and useful suggestions during this work. We are grateful to the following colleagues for providing reagents: R Nusse, K Willert, Y Ben-Neriah, S Dedhar, F Costantini, M Shtutman, A Telerman, R Amson and X He. These studies were supported by grants from The Israel Science Foundation (ISF), Israel Cancer Research Fund (ICRF), The German Israeli Foundation for Scientific Research and Development (GIF), The MD Moross Institute for Cancer Research and La Foundation Raphael et Regina Levy.

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100, Rehovot, Israel

    Elina Levina, Moshe Oren & Avri Ben-Ze'ev

Authors
  1. Elina Levina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moshe Oren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Avri Ben-Ze'ev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Avri Ben-Ze'ev.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levina, E., Oren, M. & Ben-Ze'ev, A. Downregulation of β-catenin by p53 involves changes in the rate of β-catenin phosphorylation and Axin dynamics. Oncogene 23, 4444–4453 (2004). https://doi.org/10.1038/sj.onc.1207587

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207587

Keywords

This article is cited by

Search

Advanced search

Quick links