The role of p53 in pancreatic β-cell apoptosis

Abstract

Abstract β-cells regulate glucose serum levels by means of synthesis and secretion of insulin. Chronic hyperglycemia diminishes the pancreatic β-cell mass due to an increase in the rate of apoptosis. Although the precise mechanism of glucotoxicity on the β-cells is not fully known, several mechanisms have been proposed, the most outstanding being: the increase of Reactive Oxygen Species (ROS), the loss of the mitochondrial membrane potential, and the activation of the intrinsic route of the apoptosis due to p53. This paper will focus on the mobilization and phosphorylation of p53 towards the mitochondrion, and the activation of the intrinsic route of the apoptosis by hyperglycemia. Since p53 has important functions over the regulation of the cellular cycle, proliferation, and apoptosis, it is subject to strict regulation. The degradation of p53 occurs in the proteasome, and depends on its ubiquitination by Mdm2 (murine double minute 2). Hyperglycemia affects the concentration, ubiquitination and phosphorylation of Mdm2, as well as the phosphorylation of p53, therefore also affecting its average life. Studies made by our group demonstrated that the increase of glucose promotes the interaction between p53 and Mdm2; however, the ubiquitination of p53 diminishes. Thus, it is likely that hyperglycemia interferes with the capacity of Mdm2 to ubiquitinate p53, and leads it to degradation, which allows for p53 to move towards the mitochondria, and for apoptosis activation. Knowing what mechanisms activate the death of the pancreatic β-cells, will allow proposing alternative treatment to prevent dysfunction and decreased of pancreatic β-cell.