Search

Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD + in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel-Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.

In this study, hypoxia inducible factor-1α (HIF-1α) and hypoxia inducible factor-1β (HIF-1β) from small abalone Haliotis diversicolor were cloned. The cDNA of H. diversicolor HIF-1α (HdHIF-1α) is 2,833 bp encoding a protein of 711aa and H. diversicolor HIF-1β (HdHIF-1β) is 1919 bp encoding a protein of 590aa. Similar to other species' HIF-1, HdHIF-1 has one basic helix-loop-helix (bHLH) domain and two Per-Arnt-Sim (PAS) domains, and HdHIF-1α has a oxygen-dependent degradation domain (ODDD) with two proline hydroxylation motifs and a C-terminal transactivation domain (C-TAD) with an asparagine hydroxylation motif. Under normoxic conditions, HdHIF-1α and HdHIF-1β mRNAs were constitutively present in all examined tissues. Under hypoxia (2.0mg/L DO at 25°C) stress, HdHIF-1α expression was up-regulated in gills at 4h, 24h and 96 h, and in hemocytes at 24h and 96 h, while HdHIF-1β remained relatively constant. Under thermal stress (31°C), HdHIF-1α expression was significantly increased in gills at 4h, and hemocytes at 0 h and 4 h, while HdHIF-1β expression still remained relatively constant. These results suggested that HIF-1α may play an important role in adaption to poor environment in H. diversicolor., (© 2013 Elsevier B.V. All rights reserved.)

Hypoxia is a hallmark of various ischemic diseases such as ischemic heart disease, ischemic limb, ischemic stroke, and solid tumors. Gene therapies for these diseases have been developed with various therapeutic genes including growth factors, anti-apoptotic genes, and toxins. However, non-specific expression of these therapeutic genes may induce dangerous side effects in the normal tissues. To avoid the side effects, gene expression should be tightly regulated in an oxygen concentration dependent manner. The hypoxia inducible promoters and enhancers have been evaluated as a transcriptional regulation tool for hypoxia inducible gene therapy. The hypoxia inducible UTRs were also used in gene therapy for spinal cord injury as a translational regulation strategy. In addition to transcriptional and translational regulations, post-translational regulation strategies have been developed using the HIF-1α ODD domain. Hypoxia inducible transcriptional, translational, and post-translational regulations are useful for tissue specific gene therapy of ischemic diseases. In this review, hypoxia inducible gene expression systems are discussed and their applications are introduced., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The importance of oxygen for the survival of multicellular and aerobic organisms is well established and documented. Over the years, increased knowledge of its use for bioenergetics has placed oxygen at the centre of research on mitochondria and ATP‐generating processes. Understanding the molecular mechanisms governing cellular oxygen sensing and response has allowed for the discovery of novel pathways oxygen is involved in, culminating with the award of the Nobel Prize for Medicine and Physiology in 2019 to the pioneers of this field, Greg Semenza, Peter Ratcliffe and William Kaelin. However, it is now beginning to be appreciated that oxygen can be a signalling molecule involved in a vast array of molecular processes, most of which impinge on gene expression control. This review will focus on the knowns and unknowns of oxygen as a signalling molecule, highlighting the role of 2‐oxoglutarate‐dependent dioxygenases as central players in the cellular response to deviations in oxygen tension. [ABSTRACT FROM AUTHOR]

Hypoxia is the most critical factor for maintaining stemness. During embryonic development, neural stem cells (NSCs) reside in hypoxic niches, and different levels of oxygen pressure and time of hypoxia exposure play important roles in the development of NSCs. Such hypoxic niches exist in adult brain tissue, where the neural precursors originate. Hypoxia-inducible factors (HIFs) are key transcription heterodimers consisting of regulatory α-subunits (HIF-1α, HIF-2α, HIF-3α) and a constitutive β-subunit (HIF-β). Regulation of downstream targets determines the fate of NSCs. In turn, the stability of HIFs-α is regulated by prolyl hydroxylases (PHDs), whose activity is principally modulated by PHD substrates like oxygen (O2), α-ketoglutarate (α-KG), and the co-factors ascorbate (ASC) and ferrous iron (Fe2+). It follows that the transcriptional activity of HIFs is actually determined by the contents of O2, α-KG, ASC, and Fe2+. In normoxia, HIFs-α are rapidly degraded via the ubiquitin-proteasome pathway, in which PHDs, activated by O2, lead to hydroxylation of HIFs-α at residues 402 and 564, followed by recognition by the tumor suppressor protein von Hippel–Lindau (pVHL) as an E3 ligase and ubiquitin labeling. Conversely, in hypoxia, the activity of PHDs is inhibited by low O2 levels and HIFs-α can thus be stabilized. Hence, suppression of PHD activity in normoxic conditions, mimicking the effect of hypoxia, might be beneficial for preserving the stemness of NSCs, and it is clinically relevant as a therapeutic approach for enhancing the number of NSCs in vitro and for cerebral ischemia injury in vivo. This study will review the putative role of PHD inhibitors on the self-renewal of NSCs.

Hypoxia is a common feature in solid tumors and is associated with cancer progression. The main regulators of the hypoxic response are hypoxia-inducible transcription factors (HIFs) that guide the cellular adaptation to hypoxia by gene activation. The actual oxygen sensing is performed by HIF prolyl hydroxylases (PHDs) that under normoxic conditions mark the HIF-α subunit for degradation. Cancer progression is not regulated only by the cancer cells themselves but also by the whole tumor microenvironment, which consists of cellular and extracellular components. Hypoxic conditions also affect the stromal compartment, where stromal cells are in close contact with the cancer cells. The important function of HIF in cancer cells has been shown by many animal models and described in hundreds of reviews, but less in known about PHDs and even less PHDs in stromal cells. Here, we review hypoxic signaling in tumors, mainly in the tumor stroma, with a focus on HIFs and PHDs.

Hypoxia is a common feature in solid tumors and is associated with cancer progression. The main regulators of the hypoxic response are hypoxia-inducible transcription factors (HIFs) that guide the cellular adaptation to hypoxia by gene activation. The actual oxygen sensing is performed by HIF prolyl hydroxylases (PHDs) that under normoxic conditions mark the HIF-α subunit for degradation. Cancer progression is not regulated only by the cancer cells themselves but also by the whole tumor microenvironment, which consists of cellular and extracellular components. Hypoxic conditions also affect the stromal compartment, where stromal cells are in close contact with the cancer cells. The important function of HIF in cancer cells has been shown by many animal models and described in hundreds of reviews, but less in known about PHDs and even less PHDs in stromal cells. Here, we review hypoxic signaling in tumors, mainly in the tumor stroma, with a focus on HIFs and PHDs. [ABSTRACT FROM AUTHOR]

As Nuclear Factor-κB (NF-κB) is a major transcription factor responding to cellular stress, it is perhaps not surprising that is activated by hypoxia, or decreased oxygen availability. However, how NF-κB becomes activated in hypoxia is still not completely understood. Several mechanisms have been proposed and this review will focus on the main findings highlighting the molecules that have been identified in the process of hypoxia induced NF-κB. In addition, we will discuss the role of NF-κB in the control of the cellular response to hypoxia. [ABSTRACT FROM AUTHOR]

The hypoxia signaling pathway is an evolutionarily conserved cellular signaling pathway present in animals ranging from Caenorhabditis elegans to mammals. The pathway is crucial for oxygen homeostasis maintenance. Hypoxia-inducible factors (HIF-1α and HIF-2α) are master regulators in the hypoxia signaling pathway. Oxygen concentrations vary a lot in the aquatic environment. To deal with this, fishes have adapted and developed varying strategies for living in hypoxic conditions. Investigations into the strategies and mechanisms of hypoxia adaptation in fishes will allow us to understand fish speciation and breed hypoxia-tolerant fish species/strains. This review summarizes the process of the hypoxia signaling pathway and its regulation, as well as the mechanism of hypoxia adaptation in fishes. [ABSTRACT FROM AUTHOR]

The cell cycle is an important cellular process whereby the cell attempts to replicate its genome in an error-free manner. As such, mechanisms must exist for the cell cycle to respond to stress signals such as those elicited by hypoxia or reduced oxygen availability. This review focuses on the role of transcriptional and post-transcriptional mechanisms initiated in hypoxia that interface with cell cycle control. In addition, we discuss how the cell cycle can alter the hypoxia response. Overall, the cellular response to hypoxia and the cell cycle are linked through a variety of mechanisms, allowing cells to respond to hypoxia in a manner that ensures survival and minimal errors throughout cell division. [ABSTRACT FROM AUTHOR]