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Perspectives
ARF the Integrator: Linking NF-?B, p53 and Checkpoint Kinases
Sonia Rocha and Neil D. Perkins
volume 4 | issue 6
june 2005Pages: 756-759
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The ARF tumour 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-?B 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-?B’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 proproliferative or anti-apoptotic functions. Therefore, through this mechanism, ARF can integrate the cellular response to an oncogene, thus maximising the effectiveness of the p53 tumour suppressor pathway.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.