ARF the integrator: linking NF-kappaB, p53 and checkpoint kinases.
The ARF tumor suppressor initiates the cellular response to aberrant oncogene activation through binding to and inhibiting the activity of Hdm2/Mdm2, the inhibitor of p53. However, many pathways also active in the cell will oppose p53 function if left unchecked. An example of this, is the RelA (p65) NF-kappaB subunit. Frequently activated by oncogenes, RelA is a potent inducer of anti-apoptotic gene expression, which has the potential to inhibit the pro-apoptotic functions of p53. We have recently discovered that by inducing the activity of the checkpoint kinases ATR and Chk1, ARF neutralises this opposing pathway. ARF-induced Chk1 phosphorylates RelA on threonine 505, a residue in its transactivation domain, thus inhibiting NF-kappaB's ability to stimulate anti-apoptotic gene expression. Furthermore, ARF-induced ATR is required for efficient induction and activation of p53. We propose that this pathway will target other proteins with pro-proliferative or anti-apoptotic functions. Therefore, through this mechanism, ARF can integrate the cellular response to an oncogene, thus maximising the effectiveness of the p53 tumor suppressor pathway.
Rocha
Sonia
S
Division of Gene Regulation and Expression, Dow Street, University of Dundee, School of Life Sciences, Dundee, Scotland, United Kingdom.
Perkins
Neil D
ND
D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D005786:Gene Expression Regulation; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; 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; D020727:ADP-Ribosylation Factors