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

Research output: Contribution to journalArticle

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

Fingerprint

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, Raghavendra G.; 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, RG, 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 C, Kawamori D, Liew CW, Maier B, Hu J, Keller SR et al. Δ40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. Diabetes. 2011 Apr;60(4):1210-1222. https://doi.org/10.2337/db09-1379
Hinault, Charlotte ; Kawamori, Dan ; Liew, Chong Wee ; Maier, Bernhard ; Hu, Jiang ; Keller, Susanna R. ; Mirmira, Raghavendra G. ; 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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