The tumour-suppressor p53 is not required for pancreatic β cell death during diabetes and upon irradiation

Abstract

Immune-independent diabetes often occurs via pancreatic β cell dysfunction. However, the role of the tumour suppressor p53 that regulates cellular life and death in multiple tissues, in pancreatic cell death and diabetes has not been clarified. We have therefore utilized an established mouse model for diabetes in which the MHC class I antigen is overexpressed in pancreatic β cells under the rat insulin promoter, to investigate the role of p53. We show that pancreatic β cell death, as determined by TUNEL staining, is elevated in transgenic mice compared to wild-type mice. However, there was no increase in immuno-reactivity towards anti-p53 antibodies in the pancreas of transgenic mice over the course of diabetes formation and β cell death, suggesting that p53 may not be involved in these processes. Interestingly, p53 expression was also not induced in pancreas upon γ-irradiation, which resulted in a massive increase in the number of TUNEL-positive cells, suggesting that the p53 pathway may not be causally involved in pancreatic cell death. To further confirm these findings, we generated MHC class I transgenic mice lacking p53 expression. Absence of p53 did not result in any significant changes in pancreatic morphology or affect cell death levels. Importantly, p53 absence did not rescue the diabetic phenotype of the transgenic mice. The results therefore demonstrate that p53 may not be causally involved in pancreatic β cell death, and suggests that the classical cell death pathway dependent on p53 may not be operating in pancreatic β cells. © 2008 The Authors. Journal compilation © 2008 The Physiological Society.