p14ARF regulates E2F-1 ubiquitination and degradation via a p53-dependent mechanism

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

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Alterations in the ARF tumor 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 tumors. 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 tumor 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 tumor suppressor network and is unlikely to constitute a p53-independent pathway for ARF function.

Original languageEnglish
Pages (from-to)1741-1747
Number of pages7
JournalCell Cycle
Volume6
Issue number14
Publication statusPublished - 15 Jul 2007
Externally publishedYes

Keywords

  • ARF
  • E2F-1
  • Proteasome
  • Ubiquitination

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