Regulation of E2F activity by p14ARF

The p14[ARF] product of the ink4a/arf locus is induced by a variety of oncogenic signals. p14[ARF] can facilitate growth aixest through the p53 pathway by hindering the down-regulation of p53 activity through its interaction with MDM2, which interferes with formation of the complex between p53 and MDM2. Here I have explored the possibility that p14ARF may be integrated with growth regulatory pathways other than p53, and report that p14ARF can modulate the activity of the cell cycle regulating E2F transcription factor. P14ARF regulates E2F-1 activity in both SAOS2 cells and p53-1-/mdm2-1-MEFs, excluding the possibility that the effects of on E2F are influenced by MDM2. p14ARF down regulates E2F-dependent transcription, S-phase entry, apoptosis and colony formation. The mechanism responsible for this activity may be through regulation of E2F stability at the post-translational level. P14[ARF] forms a physical complex with E2F both in vitro and in cells. binds to E2F through distinct, binding domains, one of which resides in the N-terminal region and is capable of down-regulating E2F activity. These results highlight the potential interplay and cross talk between p14[ARF] and E2F-1, and establish as an antagonist of cell growth that acts by targeting two of the key pathways involved in controlling proliferation, namely E2F and p53