It is well accepted that the Mdm2 ubiquitin ligase acts as a major factor in controlling p53 stability and activity in vivo. Although several E3 ligases have been reported to be involved in Mdm2-independnet p53 degradation, the roles of these ligases in p53 regulation in vivo remain largely unknown. To elucidate the physiological role of the ubiquitin ligase ARF-BP1, we generated arf-bp1 mutant mice. We found that inactivation of arf-bp1 during embryonic development in mice resulted in p53 activation and embryonic lethality but the mice with arf-bp1 deletion specifically in the pancreatic ß-cells (arf-bp1FL/Y/RIP-cre) were viable and displayed no obvious abnormality after birth. Interestingly, these mice showed dramatic loss of ß-cells as mice aged and more than 50% of these mice died of severe diabetic symptoms before reaching one year of age. Notably, the diabetic phenotype of these mice was largely reversed by concomitant deletion of p53 and the life-span of the mice was significantly extended (p53FL/FL/arf-bp1FL/Y/RIP-cre). These findings underscore an important role of ARF-BP1 in maintaining ß-cell homeostasis in aging mice and reveal that the stability of p53 is critically regulated by ARF-BP1 in vivo.

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