Control of metabolism by p53 - Cancer and beyond

Abstract

p53 is an important tumour suppressor gene, with loss of p53 contributing to the development of most human cancers. However, the activation of p53 in response to stress signals underpins a role for p53 in diverse aspects of health and disease. Activities of p53 that regulate metabolism can play a role in maintaining homeostasis and protecting cells from damage - so preventing disease development. By contrast, either loss or over-activation of p53 can contribute to numerous metabolic pathologies, including aging, obesity and diabetes.

Fig. 1

p53 regulates cell survival and proliferation in vitro. p53 can repress or support cell proliferation and survival depending on the cellular signal and context. Cancer associated stress signals including high ROS levels, DNA damage, oncogene activation, telomere shortening and hypoxia activate a p53 response that frequently promotes cell death and cell elimination. Metabolic stress signals including transient oxidative stress, nutrient starvation and growth factor deprivation activate a p53 response that more commonly promotes cell survival and proliferation.

Fig. 2

Regulation of energy metabolism by p53. Under conditions of metabolic stress, p53 induces catabolic pathways and autophagy to maintain energy production and cell survival while inhibiting energy and nutrient consuming anabolic pathways, cell growth and proliferation. p53 inhibits glycolysis and promotes mitochondrial respiration, while also limiting lipid biosynthesis and promoting lipolysis. Note that while oxidative phosphorylation is a major source of mitochondrial ROS, maintenance of mitochondrial health by p53 is likely to limit oxidative stress through this source. In addition to PPP activation, p53 controls ROS through numerous other mechanisms (not shown). Pathways depicted in blue are repressed by p53 while pathways depicted in red are activated by p53. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

p53 regulates stress response and homeostasis in vivo. Numerous stress signals activate p53. An optimal p53 response (green) is required to maintain whole body and tissue homeostasis. However, insufficient or excessive p53 (red) has deleterious effects and results in cell death, lipid accumulation, inflammation and compromised tissue functionality. As a consequence, failure to maintain optimal p53 levels can lead to numerous adverse pathologies, beyond cancer. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)