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:

A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1

Oncogene volume 21, pages 1469–1476 (2002)Cite this article

Abstract

p53 exerts its tumor suppressor effects by activating genes involved in cell growth arrest and programmed cell death. The p53 target genes inducing growth arrest are well defined whereas those inducing apoptosis are not fully characterized. Proapoptotic activity of p53 was shown to involve several genes like Bax, Noxa and Puma, which may function in the release of cytochrome c from the mitochondria. Cytochrome c associates with Apaf-1 and caspase 9 to form the apoptosome. Genetic and cellular data indicate that Apaf-1 deficiency abrogates the apoptotic effect of p53 and substitutes for p53 loss in promoting tumor formation. Here we show that Apaf-1, the mammalian homologue of C. elegans CED4, is a direct target of p53 as demonstrated by gel shift analysis of the target site sequence in the presence of p53 and by Apaf-1 promoter-luciferase assays. We also show that the p53 activation of the Apaf-1 luciferase construct can be enhanced by the putative tumor suppressor gene product, Zac-1, a transcription factor that has previously been shown to inhibit cell proliferation. Furthermore, we demonstrate that Zac-1 is a possible direct target of p53 since the sequence upstream to the first coding exon of Zac-1 contains a p53 recognition site and the luciferase construct containing this region is activated by p53. These results suggests the existence of a tightly controlled self amplifying mechanism of transcriptional activation leading to apoptosis by p53.

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

Similar content being viewed by others

References

  • Aravind L, Dixit VM, Konnin EV . 2001 Science 291: 1279–1284

  • Arima T, Drewell RA, Oshimura M, Wake N, Surani MA . 2000 Genomics 67: 248–255

  • Bates S, Vousden KH . 1999 Cell. Mol. Life Sci. 55: 28–37

  • Bilanges B, Varrault A, Basyuk E, Rodriguez C, Mazumdar A, Pantaloni C, Bockaert J, Theillet C, Spengler D, Journot L . 1999 Oncogene 18: 3979–3988

  • Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P . 1998 Cell 94: 727–737

  • Deng C, Zhang P, Harper JW, Elledge SJ, Leder P . 1995 Cell 82: 675–684

  • el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B . 1992 Nat. Genet. 1: 45–49

  • Gottlieb TM, Oren M . 1998 Semin. Cancer Biol. 8: 359–368

  • Gross A, McDonnell JM, Korsmeyer SJ . 1999 Genes Dev. 13: 1899–1911

  • Huang SM, Stallcup MR . 2000 Mol. Cell. Biol. 20: 1855–1867

  • Huang SM, Schonthal AH, Stallcup MR . 2001 Oncogene 20: 2134–2143

  • Jia L, Srinivasula SM, Liu FT, Newland AC, Fernandes-Alnemri R, Alnemri ES, Kelsey SM . 2001 Blood 98: 414–421

  • Jiang X, Wang X . 2000 J. Biol. Chem. 275: 31199–31203

  • Jimenez GS, Nister M, Stommel JM, Beeche M, Barcarse EA, Zhang X-Q, O'Gorman S, Wahl GM . 2000 Nat. Genet. 26: 37–43

  • Kannan K, Amariglio N, Rechavi G, Jakob-Hirsch J, Kela I, Kaminski N, Getz G, Domany E, Givol D . 2001a Oncogene 20: 2225–2234

  • Kannan K, Kaminski N, Rechavi G, Jakob-Hirsch J, Amariglio N, Givol D . 2001b Oncogene 20: 3449–3455

  • Kelekar A, Thompson CB . 1998 Trends Cell Biol. 8: 324–330

  • Levine AJ . 1997 Cell 88: 323–331

  • Miyashita T, Reed JC . 1995 Cell 80: 293–299

  • Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H, Helin K . 2001 Nat. Cell. Biol. 3: 552–558

  • Nakano K, Vousden KH . 2001 Mol. Cell 7: 683–694

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

  • Reed JC . 1999 J. Clin. Oncol. 17: 2941–2953

  • Robles AI, Bemmels NA, Foraker AB, Harris CC . 2001 Cancer Res. 61: 6660–6664

  • Samuels-Lev Y, O'Connor DJ, Bergamaschi D, Trigiante G, Hsieh JK, Zhong S, Campargue I, Naumovski L, Crook T, Lu X . 2001 Mol. Cell. 8: 781–794

  • Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW, Lowe SW . 1999 Science 284: 156–159

  • Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW . 2001 Nature 409: 207–211

  • Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J, Journot L . 1997 EMBO J. 16: 2814–2825

  • Thornborrow EC, Manfredi JJ . 1999 J. Biol. Chem. 274: 33747–33756

  • Varrault A, Bilanges B, Mackay DJG, Basyuk E, Ahr B, Fernandez C, Robinson DO, Bockaert J, Journot L . 2001 J. Biol. Chem. 276: 18653–18656

  • Varrault A, Ciani E, Apiou F, Bilanges B, Hoffmann A, Pantaloni C, Bockaert J, Spengler D, Journot L . 1998 Proc. Natl. Acad. Sci. USA 95: 8835–8840

  • Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M . 1991 Nature 352: 345–347

  • Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW . 1998 Cell 94: 739–750

  • Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B . 2001 Mol. Cell 7: 673–682

  • Zou H, Li Y, Liu X, Wang X . 1999 J. Biol. Chem. 274: 11549–11556

Download references

Acknowledgements

We thank Dr Moshe Oren for the baculovirus recombinant p53, the p53 cDNA constructs and pAb421 and for helpful discussion. We thank Dr M Stallcup for the Zac-1 construct and Dr X Wang for the Apaf-1 construct. This work was supported in part by the Arison Dorsman donation, the Yad Abraham Center for Cancer Diagnosis and Therapy and the Germany Israel Science Foundation (GIF). G Rechavi holds the Gregorio and Dora Shapiro Chair for Hematology Malignancies, Sackler School of Medicine Tel Aviv University. Part of this work was performed in partial fulfilment of the requirement of the Ph. D. degree of Galit Rozenfeld-Granot, Sackler Faculty of Medicine, Tel Aviv University.

Author information

Authors and Affiliations

  1. Department of Pediatric Hemato-Oncology, The Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Israel

    Galit Rozenfeld-Granot, Amos Toren, Ninette Amariglio & Gideon Rechavi

  2. Department of Molecular Cell Biology, Weizmann Institute of Science, Israel

    Janakiraman Krishnamurthy, Karuppiah Kannan & David Givol

Authors
  1. Galit Rozenfeld-Granot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Janakiraman Krishnamurthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karuppiah Kannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amos Toren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ninette Amariglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Givol
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gideon Rechavi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Givol.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rozenfeld-Granot, G., Krishnamurthy, J., Kannan, K. et al. A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1. Oncogene 21, 1469–1476 (2002). https://doi.org/10.1038/sj.onc.1205218

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205218

Keywords

This article is cited by

Search

Advanced search

Quick links