TY - JOUR
T1 - Δ40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice
AU - Hinault, Charlotte
AU - Kawamori, Dan
AU - Liew, Chong Wee
AU - Maier, Bernhard
AU - Hu, Jiang
AU - Keller, Susanna R.
AU - Mirmira, Raghavendra G.
AU - Scrable, Heidi
AU - Kulkarni, Rohit N.
PY - 2011/4
Y1 - 2011/4
N2 - 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. RESEARCH DESIGN AND 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.
AB - 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. RESEARCH DESIGN AND 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.
UR - http://www.scopus.com/inward/record.url?scp=79953198598&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953198598&partnerID=8YFLogxK
U2 - 10.2337/db09-1379
DO - 10.2337/db09-1379
M3 - Article
C2 - 21357466
AN - SCOPUS:79953198598
SN - 0012-1797
VL - 60
SP - 1210
EP - 1222
JO - Diabetes
JF - Diabetes
IS - 4
ER -