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, Raghu Mirmira, Heidi Scrable, Rohit N. Kulkarni

Research output: Contribution to journalArticle

35 Citations (Scopus)

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

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Protein Isoforms
Homeostasis
Cell Proliferation
Glucose
p53 Genes
Transgenic Mice
Cell Cycle
Cyclin D2
Premature Mortality
Glucose Intolerance
Organ Size
Homeobox Genes
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Transcriptional Activation
Research Design
Western Blotting
Immunohistochemistry
Apoptosis
Polymerase Chain Reaction

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., ... 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

Δ40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. / Hinault, Charlotte; Kawamori, Dan; Liew, Chong Wee; Maier, Bernhard; Hu, Jiang; Keller, Susanna R.; Mirmira, Raghu; Scrable, Heidi; Kulkarni, Rohit N.

In: Diabetes, Vol. 60, No. 4, 04.2011, p. 1210-1222.

Research output: Contribution to journalArticle

Hinault, C, Kawamori, D, Liew, CW, Maier, B, Hu, J, Keller, SR, Mirmira, R, Scrable, H & Kulkarni, RN 2011, 'Δ40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice', Diabetes, vol. 60, no. 4, pp. 1210-1222. https://doi.org/10.2337/db09-1379
Hinault, Charlotte ; Kawamori, Dan ; Liew, Chong Wee ; Maier, Bernhard ; Hu, Jiang ; Keller, Susanna R. ; Mirmira, Raghu ; Scrable, Heidi ; Kulkarni, Rohit N. / Δ40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. In: Diabetes. 2011 ; Vol. 60, No. 4. pp. 1210-1222.
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