Review
Homeostatic functions of the p53 tumor suppressor: Regulation of energy metabolism and antioxidant defense

https://doi.org/10.1016/j.semcancer.2008.11.005Get rights and content

Abstract

The p53 tumor suppressor plays pivotal role in the organism by supervising strict compliance of individual cells to needs of the whole organisms. It has been widely accepted that p53 acts in response to stresses and abnormalities in cell physiology by mobilizing the repair processes or by removing the diseased cells through initiating the cell death programs. Recent studies, however, indicate that even under normal physiological conditions certain activities of p53 participate in homeostatic regulation of metabolic processes and that these activities are important for prevention of cancer. These novel functions of p53 help to align metabolic processes with the proliferation and energy status, to maintain optimal mode of glucose metabolism and to boost the energy efficient mitochondrial respiration in response to ATP deficiency. Additional activities of p53 in non-stressed cells tune up the antioxidant defense mechanisms reducing the probability of mutations caused by DNA oxidation under conditions of daily stresses. The deficiency in the p53-mediated regulation of glycolysis and mitochondrial respiration greatly accounts for the deficient respiration of the predominance of aerobic glycolysis in cancer cells (the Warburg effect), while the deficiency in the p53-modulated antioxidant defense mechanisms contributes to mutagenesis and additionally boosts the carcinogenesis process.

Introduction

The p53 tumor suppressor plays a key role in securing genetic stability. The importance of p53 is underscored by the fact that its activity is lost in the vast majority of human cancers [1]. While in nearly half of all human cancers the p53 gene itself is mutated leading to accumulation of dysfunctional protein, in the other half there can be found other abnormalities within the p53 pathway that compromise its tumor suppressor functions [2]. Germline mutations of the p53 gene in Li-Fraumeni syndrome are associated with tremendous susceptibility to cancer [3]. Similarly, p53−/− mice demonstrate a cancer-prone phenotype and severe karyotype instability [4].

Decades of intense studies have established a role for p53 as a stress-induced protein that protects genetic stability by restricting proliferation, motility and viability of abnormal or stress-exposed cells [5]. As the p53 knockout mice look and develop normally, it was initially concluded that functions of the p53 gene are dispensable for normal physiology. Recent studies however, while not questioning the importance of stress-induced p53 in protection against cancer, suggest additional important roles for p53 in physiology of normal non-stressed cells. The p53 is tightly involved in the homeostatic regulation of energy-producing processes, coordination of overall rate of biosynthesis, and mobilization of defenses against reactive oxygen species (ROS). Together with the stress-induced functions of p53, which eliminate the effects of existing damage, the novel functions enforce preventive mechanisms that reduce probability of mutations. These functions address daily hazards to which a cell is exposed under charge of normal physiological processes. Indeed, excluding extreme conditions such as excessive radiation and treatment with genotoxic drugs, the damages generated by normal physiological processes constitute major hazards leading to cancer and driving the ageing process. In the present review we will describe recently identified mechanisms by which p53 affects the overall rate of biosynthesis, regulates energy metabolism and controls the intracellular redox status (Fig. 1).

Section snippets

Modulation of p53 activity in response to stresses

In non-stressed cells the level of p53 is low, owing to both the ubiquitin-mediated degradation in 26S proteasomes, through processes controlled by Mdm2 and some other E3 ubiquitin ligases [6], and by the ubiquitin-independent degradation by default in 20S proteasomes [7]. p53 is induced in response to genotoxic influences [8], such as γ-radiation, UV, genotoxic drugs and oxidative stress. The p53 response can be also triggered by a variety conditions that challenge genome integrity indirectly,

p53 is supervising pathways that control biosynthesis rate

Recent studies reveal that p53 has much broader capacities in controlling basic processes within the cell. Under conditions of mild physiological stresses or even without any stresses at all p53 acts to adjust overall rate of biosynthesis with energy status of the cell and the availability of nutrients, growth factors and hormones. Apparently, these activities relate to pro-survival functions of p53 that act to maintain healthy homeostasis and to delay the ageing process.

Cell growth,

Functions of the p53 tumor suppressor control aerobic respiration and glycolysis

Energy demands of cells vary substantially depending on their tissue origin, current physiological condition, proliferation status, etc. In normal cells glucose is the major external source of energy. Energy of glucose is converted into energy of ATP. Glycolysis, an ancient anaerobic process in the cytoplasm, produces two molecules of pyruvate and only two molecules of ATP. Aerobic mitochondrial respiration finalizes glucose oxidation by yielding nearly 30 molecules of ATP. Despite its high

The antioxidant function of the p53 tumor suppressor

Organisms living in aerobic conditions utilize oxygen not only for the energy production through carbon oxidation. Oxygen can be metabolized into reactive oxygen species (ROS) that are highly reactive intermediates capable of modifying numerous biological substrates. Oxidation of lipids, proteins and nucleic acids by ROS damages cellular structures and represents a major hazard that fuels the aging process and leads to numerous pathologies. Despite the formerly widespread beliefs regarding ROS

Conflict of interest

I am stating that I do not have any competing interests connected with the above publication.

Acknowledgements

This work was supported by grants from the US National Institutes of Health R01CA10490 and R01AG025278 to P.M.C., from the Russian Basic Research Fund to P.M.C and J.E.K., from the Program on Molecular and Cellular Biology by the Russian Academy of Sciences to P.M.C. and J.E.K., and from the Howard Hughes Medical Institute to P.M.C.

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