\(\Delta\)40 Isoform of p53 Controls \(\beta\)-Cell Proliferation and Glucose Homeostasis in Mice
Keller, Susanna R.
Mirmira, Raghavendra G.
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CitationHinault, Charlotte, Dan Kawamori, Chong Wee Liew, Bernhard Maier, Jiang Hu, Susanna R. Keller, Raghavendra G. Mirmira, Heidi Scrable, and Rohit N. Kulkarni. 2011. \(\Delta\)40 isoform of p53 controls \(\beta\)-cell proliferation and glucose homeostasis in mice. Diabetes 60(4): 1210-1222.
AbstractObjective: Investigating the dynamics of pancreatic \(\beta\)-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 \(\beta\)-cell proliferation and glucose homeostasis were controlled by \(\Delta\)40p53, 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 \(\Delta\)40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine \(\beta\)-cell proliferation. Results: Transgenic mice with an ectopic p53 gene encoding \(\Delta\)40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from \(\sim\)14 months of age. Consistent with a dramatic decrease in \(\beta\)-cell mass and reduced \(\beta\)-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 \(\Delta\)40p53 in \(\beta\)-cell proliferation with implications for the development of age-dependent diabetes.
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