title: Inactivation of arf-bp1 induces p53 activation and diabetic phenotypes in mice.
abstract: 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-independent 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 β-cells (arf-bp1(FL/Y)/RIP-cre) were viable and displayed no obvious abnormality after birth. Interestingly, these mice showed dramatic loss of β-cells as mice aged, and >50% of these mice died of severe diabetic symptoms before reaching 1 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 (p53(LFL/FL)/arf-bp1(FL/Y)/RIP-cre). These findings underscore an important role of ARF-BP1 in maintaining β-cell homeostasis in aging mice and reveal that the stability of p53 is critically regulated by ARF-BP1 in vivo.
authors.affiliation: Institute for Cancer Genetics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Kon
authors.forename: Jiayun
authors.initials: J
authors.lastname: Zhong
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006706:Homeostasis / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D055550:Protein Stability; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases