title: Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions.
abstract: OBJECTIVE
  Diabetes mellitus represents a significant burden on the health of the global population. Both type 1 and type 2 diabetes share a common feature of a reduction in functional beta cell mass. A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis. However, its role in islet homeostasis is not entirely clear.
  
  
  METHODS
  We generated mice with pancreas-specific deletion of Huwe1 using a Cre-loxP recombination system driven by the Pdx1 promoter (Pdx1cre (+) Huwe1 (fl/fl)) to assess the in vivo role of HUWE1 in the pancreas.
  
  
  RESULTS
  Targeted deletion of Huwe1 in the pancreas preferentially activated p53-mediated beta cell apoptosis, leading to reduced beta cell mass and diminished insulin exocytosis. These defects were aggravated by ageing, with progressive further decline in insulin secretion and glucose homeostasis in older mice. Intriguingly, Huwe1 deletion provided protection against genotoxicity, such that Pdx1cre (+) Huwe1 (fl/fl) mice were resistant to multiple-low-dose-streptozotocin-induced beta cell apoptosis and diabetes.
  
  
  CONCLUSIONS
  HUWE1 expression in the pancreas is essential in determining beta cell mass. Furthermore, HUWE1 demonstrated divergent roles in regulating beta cell apoptosis depending on physiological or genotoxic conditions.
authors: Toronto General Research Institute, University Health Network, MaRS Ctre, TMDT, 101 College St, 10th floor, Rm 10-363, Toronto, ON, Canada, M5G 1L7.
authors: Linyuan
authors: L
authors: Wang
authors: Cynthia T
authors: CT
authors: Luk
authors: Stephanie A
authors: SA
authors: Schroer
authors: Alannah M
authors: AM
authors: Smith
authors: Xie
authors: X
authors: Li
authors: Erica P
authors: EP
authors: Cai
authors: Herbert
authors: H
authors: Gaisano
authors: Patrick E
authors: PE
authors: MacDonald
authors: Zhenyue
authors: Z
authors: Hao
authors: Tak W
authors: TW
authors: Mak
authors: Minna
authors: M
authors: Woo
mesh_terms: D000818:Animals; D005260:Female; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases