View the Current Issue

Article

  • The EMBO Journal (2005) 24, 1157 - 1169
  • doi:10.1038/sj.emboj.7600608

Published online: 10 March 2005

Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor

Sonia Rocha1, Michelle D Garrett2, Kirsteen J Campbell1, Katie Schumm1 and Neil D Perkins1

  1. School of Life Sciences, Division of Gene Regulation and Expression, University of Dundee, Dundee, Scotland, UK
  2. Haddow Laboratories, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK

Correspondence to:

Neil D Perkins, Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dow Street, Dundee DD1 5EH, Scotland, UK. Tel.: +44 1382 345606; Fax +44 1382 348072; E-mail: n.d.perkins@dundee.ac.uk

Received 6 October 2004; Accepted 8 February 2005

The ARF tumour suppressor is a central component of the cellular defence against oncogene activation. In addition to activating p53 through binding Mdm2, ARF possesses other functions, including an ability to repress the transcriptional activity of the antiapoptotic RelA(p65) NF-kappaB subunit. Here we demonstrate that ARF induces the ATR- and Chk1-dependent phosphorylation of the RelA transactivation domain at threonine 505, a site required for ARF-dependent repression of RelA transcriptional activity. Consistent with this effect, ATR and Chk1 are required for ARF-induced sensitivity to tumour necrosis factor alpha-induced cell death. Significantly, ATR activity is also required for ARF-induced p53 activity and inhibition of proliferation. ARF achieves these effects by activating ATR and Chk1. Furthermore, ATR and its scaffold protein BRCA1, but not Chk1, relocalise to specific nucleolar sites. These results reveal novel functions for ARF, ATR and Chk1 together with a new pathway regulating RelA NF-kappaB function. Moreover, this pathway provides a mechanism through which ARF can remodel the cellular response to an oncogenic challenge and execute its function as a tumour suppressor.

  • Keywords:

    • ARF,
    • ATR,
    • Chk1,
    • NF-kappaB,
    • p53