Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor.
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.
Rocha
Sonia
S
School of Life Sciences, Division of Gene Regulation and Expression, University of Dundee, Dundee, Scotland, UK.
Garrett
Michelle D
MD
Campbell
Kirsteen J
KJ
Schumm
Katie
K
Perkins
Neil D
ND
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000032:analysis / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002466:Cell Nucleolus / Q000737:chemistry; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D051996:Transcription Factor RelA; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D013912:Threonine; D012694:Serine; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases