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p14ARF Regulates E2F-1 Ubiquitination and Degradation via a p53-Dependent Mechanism

Helen Rizos, Lyndee L. Scurr, Mal Irvine, Nikki J. Alling and Richard F. Kefford

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Alterations in the ARF tumour suppressor protein (also known as p14ARF in humans and p19ARF in the mouse) occur frequently in cancer and are associated with susceptibility to melanoma, pancreatic cancer and nervous system tumours. ARF proteins interact with the E2F-1, -2 and -3 transcription activators to inhibit their transcriptional activity and induce their degradation via the 26S proteasome pathway. The impact of ARF on the E2F proteins may provide a mechanism for p53-independent ARF activity on cell cycle progression and tumour susceptibility. In this report we explored the effects of ARF on E2F ubiquitination and degradation in relationship to cell cycle effects and p53 status. We now show that ARF induced the rapid ubiquitination and degradation of E2F-1 only in the presence of functional p53. E2F-1 continued to be ubiquitinated following ARF induction in cycling p53-wild-type, p21-null cells, showing that effects of ARF were not simply a result of p14ARF induced cell-cycle arrest. Importantly, these data establish that the ARF-E2F-1 pathway is an extension of the p53-mdm2-ARF tumour suppressor network and is unlikely to constitute a p53-independent pathway for ARF function.

Authors

Helen Rizos

University of Sydney

Lyndee L. Scurr

University of Sydney; Westmead, Australia

Mal Irvine

University of Sydney; Westmead, Australia

Nikki J. Alling

University of Sydney; Westmead, Australia

Richard F. Kefford

University of Sydney; Westmead, Australia

Purchase article for $19

Subscribe to this journal for $129/year