Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.

A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response

The hallmarks of cancer metabolism: Still emerging.

Most introductory biology and biochemistry courses focus on glycolysis (oxidation of glucose to pyruvate) and the TCA cycle (oxidation of pyruvate to acetyl-CoA and the eventual complete oxidation to CO2). While these are extremely important and universal reactions, most courses leave out the pentose phosphate pathway (PPP) or hexose monophosphate shunt. This pathway, like the TCA cycle, is partially cyclic in nature in which three glucose molecules enter and two glucose and one glyceraldyde-3-phosphate (G3P) leave. The two glucose molecules can recycle, and the G3P enters glycolysis. Its an important pathway because it is the primary mechanism for the formation of pentoses, the five-carbon sugar required for nucleotide biosynthesis as well as the formation of a variety of other essential cellular components and NADPH, the cellular reductant primarily used in anabolic reactions.

Pentose phosphate pathway

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed. 

/pdf/hypoxia-inducible-factors-cancer-progression-and-clinical-2yamuqve.pdf

Hypoxia-inducible factors: cancer progression and clinical translation

Abstract The immune-inflammatory response is associated with increased nitro-oxidative stress. The aim of this mechanistic review is to examine: (a) the role of redox-sensitive transcription factors and enzymes, ROS/RNS production, and the activity of cellular antioxidants in the activation and performance of macrophages, dendritic cells, neutrophils, T-cells, B-cells, and natural killer cells; (b) the involvement of high-density lipoprotein (HDL), apolipoprotein A1 (ApoA1), paraoxonase-1 (PON1), and oxidized phospholipids in regulating the immune response; and (c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor-κB, HIF1α, the mechanistic target of rapamycin, the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, mitogen-activated protein kinases, 5' AMP-activated protein kinase, and peroxisome proliferator-activated receptor. The performance and survival of individual immune cells is under redox control and depends on intracellular and extracellular levels of ROS/RNS. They are heavily influenced by cellular antioxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2, and the HDL/ApoA1/PON1 complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance. 

/pdf/redox-regulation-of-the-immune-response-2d14x08r.pdf

Redox regulation of the immune response

Under conditions of hypoxia, most eukaryotic cells can shift their primary metabolic strategy from predominantly mitochondrial respiration towards increased glycolysis to maintain ATP levels. This hypoxia-induced reprogramming of metabolism is key to satisfying cellular energetic requirements during acute hypoxic stress. At a transcriptional level, this metabolic switch can be regulated by several pathways including the hypoxia inducible factor-1α (HIF-1α) which induces an increased expression of glycolytic enzymes. While this increase in glycolytic flux is beneficial for maintaining bioenergetic homeostasis during hypoxia, the pathways mediating this increase can also be exploited by cancer cells to promote tumour survival and growth, an area which has been extensively studied. It has recently become appreciated that increased glycolytic metabolism in hypoxia may also have profound effects on cellular physiology in hypoxic immune and endothelial cells. Therefore, understanding the mechanisms central to mediating this reprogramming are of importance from both physiological and pathophysiological standpoints. In this review, we highlight the role of HIF-1α in the regulation of hypoxic glycolysis and its implications for physiological processes such as angiogenesis and immune cell effector function.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP280572

S. J. Kierans

Papers

Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology.