p14ARF regulates E2F activity

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Abstract
The ARF protein product of the ink4a/arf locus is induced by a variety of oncogenic signals. ARF facilitates growth arrest through the p53 pathway by hindering the down-regulation of p53 activity mediated by MDM2, through the formation of a protein complex with MDM2. Here we have explored the possibility that human p14ARF activity is integrated with growth regulating pathways other than p53, and report our results that p14ARF can control the activity of the E2F transcription factor. p14ARF regulates E2F activity in different cell-types, including p53−/−/mdm−/− MEFs, thus excluding that the effects of p14ARF are indirectly caused through MDM2 modulation. p14ARF down-regulates E2F-dependent transcription, and in cells undergoing E2F-dependent apoptosis prompts cell cycle arrest. p14ARF possesses multiple binding domains for E2F-1, one of which resides within the N-terminal region and coincides with the regulation of E2F activity. A mutational analysis of p14ARF indicates that the E2F-1 and MDM2 binding domains can be distinguished. These results highlight the potential interplay between p14ARF and E2F, and establish p14ARF as a pleiotrophic regulator of cell growth that acts by targetting at least two key pathways in the control of proliferation, namely E2F and p53.