Δ40 Isoform of p53 Controls β-Cell Proliferation and Glucose Homeostasis in Mice
- Charlotte Hinault1,
- Dan Kawamori1,
- Chong Wee Liew1,
- Bernhard Maier2,
- Jiang Hu1,
- Susanna R. Keller3,
- Raghavendra G. Mirmira2,
- Heidi Scrable3 and
- Rohit N. Kulkarni1⇓
- 1Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- 2Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
- 3Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota
- Corresponding author: Rohit N. Kulkarni, .
R.G.M. and H.S. contributed equally to this article.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db09-1379/-/DC1.
- Received September 17, 2009.
- Accepted January 20, 2011.
- © 2011 by the American Diabetes Association.
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