Metabolic regulation by p53 family members

Abstract

The function of p53 is best understood in response to genotoxic stress, but increasing evidence suggests that p53 also plays a key role in the regulation of metabolic homeostasis. p53 and its family members directly influence various metabolic pathways, enabling cells to respond to metabolic stress. These functions are likely to be important for restraining the development of cancer but could also have a profound effect on the development of metabolic diseases, including diabetes. A better understanding of the metabolic functions of p53 family members may aid in the identification of therapeutic targets and reveal novel uses for p53-modulating drugs.

Figure 1

Outline of the Interaction between p53 Family Members and Metabolic Pathways p53 and its family members p63 and p73 have been implicated in many aspects of cellular metabolism, including AMPK and mTOR signalling, carbohydrate and lipid metabolism, the regulation of autophagy, and the maintenance of mitochondrial integrity and REDOX balance.

Figure 2

Outline of the Crosstalk between p53 Family Members and the mTORC1 Pathway p53 and p63 act upstream of mTORC1 and inhibit mTORC1 activity via multiple transcriptional targets. p53, p63, and p73 can all be modulated by the AMPK/mTORC1 pathway (indicated in red and blue, respectively) and link mTORC1 signalling to multiple downstream effects, including, but not limited to, cell-cycle control (via p53), autophagy (via p73), and differentiation (via p63).

Figure 3

Outline of the Regulation of Central Carbohydrate Metabolism by p53 p53 generally dampens aerobic glycolysis (blue) and promotes mitochondrial respiration (green) through multiple mechanisms, although it can both positively and negatively modulate PPP activity.

Figure 4

Outline of the Regulation of Lipid Metabolism by p53 p53 generally functions as a negative regulator of lipid synthesis by enhancing fatty acid oxidation (red) and inhibiting fatty acid synthesis (blue) through multiple mechanisms.