Δ40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice

Charlotte Hinault, Dan Kawamori, Chong Wee Liew, Bernhard Maier, Jiang Hu, Susanna R. Keller, Raghavendra G. Mirmira, Heidi Scrable, Rohit N. Kulkarni

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37 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)1210-1222
Number of pages13
JournalDiabetes
Volume60
Issue number4
DOIs
StatePublished - Apr 1 2011

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Hinault, C., Kawamori, D., Liew, C. W., Maier, B., Hu, J., Keller, S. R., Mirmira, R. G., Scrable, H., & Kulkarni, R. N. (2011). Δ40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. Diabetes, 60(4), 1210-1222. https://doi.org/10.2337/db09-1379