Transcriptional regulation of Arf Transcriptional control is the most important mechanism of Arf regulation since it has a relatively long half life of 6 hrs 23 Arf reviewed in refs 1 3 10 13 24 A number of transcription factors regulate Arf either positively or negatively Fig 1 The E2F1 transcription factor induces Arf transcription by directly binding to its consensus sequences 25 26 and also the Sp1 sites 27 which are located in the upstream of the exon 1 β thus activating cell growth arrest or apoptosis to avoid the emergence of incipient cancer cells 1 2 E2F2 and E2F3a also transactivates the Arf promoter 26 however this process is modulated differently by the various E2F isoforms For instance E2F3b a splice isoform of E2F3a that is not regulated by E2Fs represses Arf transcription and stimulates cellular growth 28 29 The observation that the loss of Arf can rescue E2F3b depletion mediated cell cycle arrest suggests anti reciprocal correlation between these two proteins 29 To prevent hyperproliferation of cells with oncogenic stress c Myc activates fail safe programs such as apoptosis and cellular senescence by inducing Arf transcription 30 Thus Myc induced Arf activates the p53 signaling preventing immortalization of the murine embryonic fibroblasts MEFs Bouchard et al reported that c Myc signaling increases nuclear FoxO which in turn binds to the Arf promoter to suppresses c Myc driven lymphomagenesis 31 Qi et al showed that Arf inhibits c Myc through physical interaction that is independent of p53 32 When c Myc increases Arf binds to c Myc to block c its ability to activate transcription induce hyperproliferation and transformation In contrast c Myc s ability to repress transcription is unaffected by Arf and c Myc mediated cell death is rather enhanced 32
