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Review
. 2016 Nov;231(2):R61-R75.
doi: 10.1530/JOE-16-0324. Epub 2016 Sep 9.

The role of the p53 tumor suppressor in metabolism and diabetes

Che-Pei Kung  1 , Maureen E Murphy  1
Affiliations
Review

The role of the p53 tumor suppressor in metabolism and diabetes

Che-Pei Kung et al. J Endocrinol. 2016 Nov.

Abstract

In the context of tumor suppression, p53 is an undisputedly critical protein. Functioning primarily as a transcription factor, p53 helps fend off the initiation and progression of tumors by inducing cell cycle arrest, senescence or programmed cell death (apoptosis) in cells at the earliest stages of precancerous development. Compelling evidence, however, suggests that p53 is involved in other aspects of human physiology, including metabolism. Indeed, recent studies suggest that p53 plays a significant role in the development of metabolic diseases, including diabetes, and further that p53's role in metabolism may also be consequential to tumor suppression. Here, we present a review of the literature on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis and insulin resistance. Additionally, we discuss the emerging role of genetic variation in the p53 pathway (single-nucleotide polymorphisms) on the impact of p53 in metabolic disease and diabetes. A better understanding of the relationship between p53, metabolism and diabetes may one day better inform the existing and prospective therapeutic strategies to combat this rapidly growing epidemic.

Keywords: diabetes; insulin resistance; metabolism; p53.

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Conflict of interest statement

Declaration of Interest The authors declare there are no conflicts of interest.

Figures

Figure 1
Figure 1. p53 structure and function
A. Functional domains of p53. Outlined are the domains responsible for transactivation (TA1 and TA2), the codon 72 polymorphism (P72R), the DNA binding domain (DBD, with some of the most common p53 ‘hotspot’ mutations shown), the oligomerization domain (OD), and the non-specific DNA binding domain (NSD). B. Overview of the p53 pathway. Ub’n: ubiquitin
Figure 2
Figure 2. The regulation of pancreatic function by p53
In response to extrinsic (hyperglycemia, free fatty acid, inflammation) and intrinsic (ER stress) stresses (colored red), p53 is activated to trigger pancreatic dysfunction and impair insulin production through several mechanisms. The genes depicted in squares represent transcriptional targets of p53. The genes colored in blue positively contribute to p53 activation, while genes colored in orange inhibit p53-mediated pancreatic dysfunction. Note that the KATP channel only activates p53 signaling in response to excessive ATP. FFA, free fatty acid; ROS, reactive oxygen species.
Figure 3
Figure 3. Three pathways for the p53-mediated regulation of glucose homeostasis
Wild-type p53 generally functions to induce circulating glucose level by (A) suppressing glucose uptake; (B) inhibiting aerobic glycolysis; and (C) promoting gluconeogenesis. The genes in squares represent transcriptional targets of p53. In (A), the genes colored in orange and blue represent positive and negative regulators of glucose uptake, respectively. In (B), the genes colored in orange and blue represent positive and negative regulators of glycolysis. In (C), the genes colored in blue represents positive regulators of gluconeogenesis. PPP, pentose phosphatase pathway; TCA cycle, the citric acid cycle; PDH, pyruvate dehydrogenase; PG, phosphoglycerate.
Figure 4
Figure 4. The regulation of insulin resistance by p53
The activation of p53 induces insulin resistance through multiple tissues/organs, including adipose tissue, liver, skeletal muscle, endothelial cells, and the brain. Cross-talk between these tissues also occurs; for example endothelial cell-mediated insulin resistance in the skeletal muscle occurs via reduction in the former of eNOS and PGC-1α. ALD, alcoholic liver disease; NAFLD, non-alcoholic fatty liver disease.
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