title: Δ40 Isoform of p53 controls β-cell proliferation and glucose homeostasis in mice.
abstract: OBJECTIVE
  Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that β-cell proliferation and glucose homeostasis were controlled by Δ40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice.
  
  
  METHODS
  We phenotyped metabolic parameters in Δ40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine β-cell proliferation.
  
  
  RESULTS
  Transgenic mice with an ectopic p53 gene encoding Δ40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from ∼14 months of age. Consistent with a dramatic decrease in β-cell mass and reduced β-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased.
  
  
  CONCLUSIONS
  These data indicate a significant and novel role for Δ40p53 in β-cell proliferation with implications for the development of age-dependent diabetes.
authors.affiliation: Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hinault
authors.forename: Dan
authors.initials: D
authors.lastname: Kawamori
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Bernhard
authors.initials: B
authors.lastname: Maier
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Keller
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.forename: Heidi
authors.initials: H
authors.lastname: Scrable
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D005947:Glucose