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Regulation of NF‐κB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor
Author(s) -
Rocha Sonia,
Garrett Michelle D,
Campbell Kirsteen J,
Schumm Katie,
Perkins Neil D
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600608
Subject(s) - biology , suppressor , nf κb , nfkb1 , cancer research , microbiology and biotechnology , genetics , signal transduction , transcription factor , gene
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‐κB 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 α‐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‐κB 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.