Regulation of Metabolic Activity by p53

Abstract

Metabolic reprogramming in cancer cells is controlled by the activation of multiple oncogenic signalling pathways in order to promote macromolecule biosynthesis during rapid proliferation. Cancer cells also need to adapt their metabolism to survive and multiply under the metabolically compromised conditions provided by the tumour microenvironment. The tumour suppressor p53 interacts with the metabolic network at multiple nodes, mostly to reduce anabolic metabolism and promote preservation of cellular energy under conditions of nutrient restriction. Inactivation of this tumour suppressor by deletion or mutation is a frequent event in human cancer. While loss of p53 function lifts an important barrier to cancer development by deleting cell cycle and apoptosis checkpoints, it also removes a crucial regulatory mechanism and can render cancer cells highly sensitive to metabolic perturbation. In this review, we will summarise the major concepts of metabolic regulation by p53 and explore how this knowledge can be used to selectively target p53 deficient cancer cells in the context of the tumour microenvironment.

p53 Expression Activation of HIV-1 Latency in U1 Cells

“…Cellular stresses, such as DNA damage, cause stabilization and activation of the p53 tumor suppressor protein [5]. The genes regulated by p53 include genes encoding cell surface proteins, mitochondrial proteins and cytoplasmic proteins.…”

“…The p53-mediated transcriptional response to DNA damage is extremely complex. P53-regulated gene expression patterns differ not only in different cell types but also in response to different induction signals, resulting in one of two different outcomes including cell cycle arrest or apoptotic cell death [5]. Cell death induced by p53 is executed by the caspase proteases, which, by cleaving their substrates, lead to the characteristic apoptotic phenotype.…”

“…Cell death induced by p53 is executed by the caspase proteases, which, by cleaving their substrates, lead to the characteristic apoptotic phenotype. Caspase activation by p53 results in the release of apoptogenic factors from the mitochondria [5]. Infection with HIV results in the progressive destruction of CD4 T lymphocytes as well as other immune responder cells [32].…”

“…As a regulator of cell proliferation, apoptosis and senescence, p53 has expanded greatly to be involved in many biological processes as well as external and internal stress responses [5]. p53 plays important roles in immune-related processes such as inflammation, innate and adaptive responses as well as functional interactions of p53 with NF-κB, which is considered a key regulator in immune responses [5]. HIV-1 infection is able to induce cytotoxic stresses linked to p53 activation in CD4+ T cells by integration mediated-dsDNA strands break [6].…”

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

“…If the reason for hypersensitivity of canine CH to HD DHEA turns out to be that CH tumors have IDH mutations, then our data in canines may translate to a wide array of currently treatment-refractory human tumors known to have such mutations. 75 The p53 tumor suppressor is the most frequently mutated gene in human cancer, 76 and its experimental manipulation in laboratory mice has provided some of the bedrock theory behind both basic science and treatment models of human cancer. If a p53 back-up role for DHEA is proven, an unfortunate consequence would be that, since much of this bedrock theory of p53 function is based on animal models lacking circulating DHEAS, and therefore the appropriate evolutionary context for human comparison, much of it could be called into question.…”