ARF the Integrator: Linking NF-?B, p53 and Checkpoint Kinases

Abstract

The ARF tumour suppressor initiates the cellular response to aberrant oncogeneactivation through binding to and inhibiting the activity of Hdm2/Mdm2, the inhibitor ofp53. However, many pathways also active in the cell will oppose p53 function if leftunchecked. An example of this, is the RelA(p65) NF-?B subunit. Frequently activatedby oncogenes, RelA is a potent inducer of anti-apoptotic gene expression, which has thepotential to inhibit the pro-apoptotic functions of p53. We have recently discovered thatby inducing the activity of the checkpoint kinases ATR and Chk1, ARF neutralises thisopposing pathway. ARF-induced Chk1 phosphorylates RelA on threonine 505, a residuein its transactivation domain, thus inhibiting NF-?B’s ability to stimulate anti-apoptoticgene expression. Furthermore, ARF-induced ATR is required for efficient induction andactivation of p53. We propose that this pathway will target other proteins with proproliferativeor anti-apoptotic functions. Therefore, through this mechanism, ARF canintegrate the cellular response to an oncogene, thus maximising the effectiveness of thep53 tumour suppressor pathway.