The p53 Pathway and Metabolism: The Tree That Hides the Forest

Abstract

The p53 pathway is functionally inactivated in most, if not all, human cancers. The p53 protein is a central effector of numerous stress-related molecular cascades. p53 controls a safeguard mechanism that prevents accumulation of abnormal cells and their transformation by regulating DNA repair, cell cycle progression, cell death, or senescence. The multiple cellular processes regulated by p53 were more recently extended to the control of metabolism and many studies support the notion that perturbations of p53-associated metabolic activities are linked to cancer development, as well as to other pathophysiological conditions including aging, type II diabetes, and liver disease. Although much less documented than p53 metabolic activities, converging lines of evidence indicate that other key components of this tumor suppressor pathway are also involved in cellular metabolism through p53-dependent as well as p53-independent mechanisms. Thus, at least from a metabolic standpoint, the p53 pathway must be considered as a non-linear pathway, but the complex metabolic network controlled by these p53 regulators and the mechanisms by which their activities are coordinated with p53 metabolic functions remain poorly understood. In this review, we highlight some of the metabolic pathways controlled by several central components of the p53 pathway and their role in tissue homeostasis, metabolic diseases, and cancer.

Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1–AKT–p53 Interactions

“…Since p53 is a master regulator of the cell cycle and survival amid DNA damage, we asked whether high-grade TP53 mutant UCs harbor defects in DDR increasing susceptibility to DDR targeted therapies [ 7 , 8 , 9 ], which target defects in repair of double strand DNA breaks (DSB) by HR and protection of stalled replication forks [ 26 ]. Functional assays for HR defects include (1) assessing tumor cell formation of post-damage RAD51 nuclear foci, and (2) challenging cells with DSB inducing agents such as gamma irradiation, PARP inhibitors, and platinum crosslinking agents [ 27 ].…”

“…In ARK1, AN3CA, and SPEC2, this upregulated band appeared as a doublet or a smear, suggesting that the mutant p53 was undergoing some form of post-translational modification in response to Alisertib. Indeed, p53 is phosphorylated during cell cycle arrest or other states of cellular stress releasing it from control by its regulatory partner MDM2 [ 7 , 8 , 45 , 46 ]. Thus, we tested for phosphorylation of mutant p53 after treatment.…”

“…TP53 mutations are one of the most common genomic alterations across all high-grade UC subtypes and associate with higher mortality; however, the functional and therapeutic relevance of these alterations remains ambiguous [ 4 , 6 ]. p53 has been widely studied across every malignancy and has many functions during cellular stress, including cell cycle arrest or apoptosis after DNA damage [ 7 , 8 , 9 ]. However, DNA damage repair (DDR) capacity and cell cycle checkpoint integrity across TP53 mutant uterine tumors has not been fully characterized.…”

p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies

“…Recent research has shown that the p53 family of proteins is involved in the transactivation of metabolic enzymes included in glucose, nucleotide, amino-acid, and lipid metabolism, as well as mitochondrial metabolism and autophagy [207][208][209]. Consequently, in human tumors, particularly CRC, the loss of tumor suppressor activity of p53 and changes in signaling pathways associated with oncogenes MYC, HIF, and KRAS, as well as PI3K/AKT/mTOR axis, are known to play a role in deregulated cellular energetics, an established hallmark of cancer [210][211][212].…”

Dynamics of p53 DNA binding sites contributes to functional selectivity of p53-driven gene expression

“…p53 is currently viewed more as the "guardian of homeostasis", rather than the "guardian of the genome" (8). It is now appreciated that p53 respond both to acute DNA damage and other life and death decisions, as well as to more "routine" activities, such as energy metabolism (9)(10)(11)(12) and embryonic development (13). In most of its activities p53 has both positive as well as negative outcomes, such as apoptosis and anti-apoptosis (14)(15)(16).…”