Tumor suppressor p53 and its mutants in cancer metabolism

Abstract

Tumor-suppressor p53 plays a key role in tumor prevention. As a transcription factor, p53 transcriptionally regulates its target genes to initiate different biological processes in response to stress, including apoptosis, cell cycle arrest or senescence, to exert its function in tumor suppression. Recent studies have revealed that metabolic regulation is a novel function of p53. Metabolic changes have been regarded as a hallmark of tumors and a key contributor to tumor development. p53 regulates many different aspects of metabolism, including glycolysis, mitochondrial oxidative phosphorylation, pentose phosphate pathway, fatty acid synthesis and oxidation, to maintain the homeostasis of cellular metabolism, which contributes to the role of p53 in tumor suppression. p53 is frequently mutated in human tumors. In addition to loss of tumor suppressive function, tumor-associated mutant p53 proteins often gain new tumorigenic activities, termed gain-of-function of mutant p53. Recent studies have shown that mutant p53 mediates metabolic changes in tumors as a novel gain-of-function to promote tumor development. Here we review the functions and mechanisms of wild-type and mutant p53 in metabolic regulation, and discuss their potential roles in tumorigenesis.

Introduction

As the “guardian of the genome”, p53 plays a key role in maintaining genomic stability and tumor prevention, which has been clearly demonstrated by following evidence from both human tumors and mouse models. p53 is frequently mutated in human tumors; somatic p53 mutations occur in almost every type of human tumors and in over 50% of all tumors [1], [2], [3]. In those tumors with low p53 mutation rates, p53 is often inactivated by alternative mechanisms. For instance, p53 can be inactivated and degraded by human papillomavirus E6 protein (HPV-E6) in cervical cancer which has a low p53 mutation rate [4], [5]. The germline p53 mutations in human beings cause a hereditary cancer predisposition syndrome, Li–Fraumeni syndrome, which leads to the development of various types of tumors in 50% of the patients by the age of 30 and 90% of patients by the age of 60 [6]. Similarly, p53 knockout mice are extremely prone to tumor development; most p53−/− mice develop tumors (principally lymphomas and sarcomas) within 6 months of age, and p53+/− mice develop tumors within one year of age [7], [8]. As a transcription factor, p53 mainly exerts its tumor suppressive function through transcriptional regulation of its target genes. In normal unstressed cells, p53 protein is kept at a low level by its negative regulators, such as Mdm2, COP1 and Pirh2, which are E3 ubiquitin ligases for p53 and degrade p53 through the proteasome degradation pathway [9], [10]. In response to a variety of stress signals arising from both intracellular and extracellular environments, including DNA damage, nutrient deprivation, hypoxia and oncogene activation, p53 protein is stabilized mainly through post-translational modifications, which leads to p53 protein activation and accumulation in cells [1], [11], [12]. Once activated, p53 binds to a specific degenerative DNA sequence, termed the p53-responsive element (p53 RE), in its target genes to regulate the expression of these genes [12], [13]. Depending on the cell and tissue types, the type and intensity of stress signals, through the regulation of a group of its target genes, p53 selectively regulates cell cycle arrest, DNA repair, apoptosis, or senescence to maintain genomic integrity and prevent tumor formation. For instance, in response to mild or transient stress signals, p53 induces its target genes involved in cell cycle arrest (e.g. p21, Gadd45, and 14-3-3σ) and DNA repair (e.g. p48, and p53R2) to allow cells to survive until the damage has been repaired or stress has been removed [11], [12], [14]. In response to severe or sustained stress signals, p53 usually induces genes involved in apoptosis (e.g. Puma, Bax, Fas, PIG3, and Killer/DR5) and senescence (e.g. p21), and therefore, prevents the accumulation of damaged cells [11], [12], [14] (Fig. 1).

Metabolic changes are a hallmark of tumor cells, which has been recently regarded as a key contributor to tumor progression [15], [16], [17]. The rapid growth and division of tumor cells requires energy and precursors for macromolecule biosynthesis. To meet the energetic and biosynthetic demands, tumor cells often display fundamental changes in metabolism. Interestingly, recent studies have revealed a novel function of p53 in regulation of metabolism, including the regulation of glycolysis, pentose phosphate pathway, mitochondrial oxidative phosphorylation and lipid metabolism, which contributes to the role of p53 in tumor suppression. In this review, we present an overview of the function and mechanism of p53 in regulating metabolism, as well as the gain-of-function oncogenic activity of mutant p53 in mediating metabolic changes in tumors.