Prolyl 4-hydroxylase activity-responsive transcription factors: From hydroxylation to gene expression and neuroprotection

Abstract

Most homeostatic processes including gene transcription occur as a result of deviations in physiological tone that threatens the survival of the organism. A prototypical homeostatic stress response includes changes in gene expression following alterations in oxygen, iron or 2-oxoglutarate levels. Each of these cofactors plays an important role in cellular metabolism. Accordingly, a family of enzymes known as the Prolyl 4-hydroxylase (PHD) enzymes are a group of dioxygenases that have evolved to sense changes in 2-oxoglutarate, oxygen and iron via changes in enzyme activity. Indeed, PHDs are a part of an established oxygen sensor system that regulates transcriptional regulation of hypoxia/stress-regulated genes and thus are an important component of events leading to cellular rescue from oxygen, iron or 2-oxoglutarate deprivations. The ability of PHD activity to regulate homeostatic responses to oxygen, iron or 2-oxoglutarate metabolism has led to the development of small molecule inhibitors of the PHDs as a strategy for activating or augmenting cellular stress responses. These small molecules are proving effective in preclinical models of stroke and Parkinson's disease. However the precise protective pathways engaged by PHD inhibition are only beginning to be defined. In the current review, we summarize the role of iron, 2-oxoglutarate and oxygen in the PHD catalyzed hydroxylation reaction and provide a brief discussion of some of the transcription factors that play an effective role in neuroprotection against oxidative stress as a result of changes in PHD activity.

Essential Role for Zinc-Triggered p75NTRActivation in Preconditioning Neuroprotection

“…In addition, in cultured cortical neurons, zinc is more effective than excitotoxins in inducing HSP70 . Whereas present results suggest that HSP70 induction by zinc is involved in ischemic or Zn PC mainly by limiting caspase-3 activation, other effects such as stabilization of hypoxia-inducible factor and activation of downstream neuroprotective genes may also contribute to PC protection (Siddiq et al, 2008).…”

Neuronal-Specific Iron Deficiency Dysregulates Mammalian Target of Rapamycin Signaling during Hippocampal Development in Nonanemic Genetic Mouse Models

“…Our group has also demonstrated downregulation of mTOR pathway genes and S6K phosphorylation in the hippocampus of P15 rats with severe dietary IDA, where tissue hypoxia is a prominent feature (12,26). mTOR downregulation in severe IDA is not surprising, because the condition causes reduced BDNF and insulin-like growth factor concentrations and lower cytochrome c oxidase activity and HIF1a activation, which can all act to suppress mTOR activity by modulating activity of upstream regulators Akt, ddit4, and AMPK (6,8,12,34). These would inhibit dendritogenesis and reduce electrophysiologic output (14,(46)(47)(48)(49).…”

“…It is found in globin oxygen transport proteins and is a cofactor for the activity of prolyl-hydroxylase, which regulates HIF1a stability (8). Mitochondrial enzymes, including cytochromes, NADPH, and flavoproteins, require iron in the form of heme and iron-sulfur clusters (9), which are integral for oxidative phosphorylation and ATP production.…”

Molecularization in nutritional science: A view from philosophy of science

“…Genetic reductionism such as it has spread in Excursus 3. The function of L-ascorbic acid (Asc) in the human organism [115][116][117][118] BLAST-based sequence comparisons suggest that the human genome does not contain any L-gulonolactone oxidase (GLO) ''coding'' gene. This means that in human tissues GLO activity cannot be detected.…”