Linkage of Pteridine Metabolism to Iron Homeostasis

Pteridines ◽  
2004 ◽  
Vol 15 (3) ◽  
pp. 120-125
Author(s):  
Günter Weiss
Keyword(s):  
Iron Homeostasis ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Central Component ◽  
Regulation Of Transcription ◽  
Binding Affinities ◽  
Hypoxia Inducible Factor 1 ◽  
Proliferation And Differentiation ◽  
Inducible Genes ◽  
Essential Growth

Abstract Iron is an essential growth factor for the proliferation and differentiation of all living cells in being centrally involved in oxygen transport by hemoglobin and myoglobin, in electron transport during mitochondrial respiration as being a part of complex I and II enzymes or in the regulation of transcription via its role as central component of ribonucelotid reductase (1,2). Moroever, iron plays a critical role in macrophage mediated cytotoxicity by contributing to the production of highly toxic hydroxy radical species needed for host defense (3). In addition, radicals formed by the catalytic action of by iron can modulate the binding affinities of several transcription factors to their target promoter region, such as hypoxia inducible factor -1 or nuclear factor-kB, thus affecting transcription of stress inducible genes (4-6).

scholarly journals Multi-Omic Meta-Analysis of Transcriptomes and the Bibliome Uncovers Novel Hypoxia-Inducible Genes

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 582
Author(s):  
Yoko Ono ◽  
Hidemasa Bono
Keyword(s):  
Meta Analysis ◽  
Hypoxia Inducible Factor ◽  
Data Driven ◽  
Similarity Coefficients ◽  
Hypoxia Inducible Factor 1 ◽  
Response System ◽  
Inducible Genes ◽  
The Relationship ◽  
G Protein Coupled ◽  
Sufficient Oxygen

Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data provides information about the relationship between genes and publications. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation.

scholarly journals Hypoxia-inducible Factor-1 Deficiency Results in Dysregulated Erythropoiesis Signaling and Iron Homeostasis in Mouse Development

2006 ◽  
Vol 281 (35) ◽  
pp. 25703-25711 ◽  
Author(s):  
Donghoon Yoon ◽  
Yves D. Pastore ◽  
Vladimir Divoky ◽  
Enli Liu ◽  
Agnieszka E. Mlodnicka ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Hypoxia Inducible Factor ◽  
Mouse Development ◽  
Hypoxia Inducible Factor 1

scholarly journals 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

2012 ◽  
Vol 113 (9) ◽  
pp. 1343-1352 ◽  
Author(s):  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Arterial ◽  
Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

scholarly journals Hypoxia-inducible factor-1 mediates adaptive developmental plasticity of hypoxia tolerance in zebrafish, Danio rerio

2014 ◽  
Vol 281 (1786) ◽  
pp. 20140637 ◽  
Author(s):  
Cayleih E. Robertson ◽  
Patricia A. Wright ◽  
Louise Köblitz ◽  
Nicholas J. Bernier
Keyword(s):  
Danio Rerio ◽  
Cellular Response ◽  
Developmental Plasticity ◽  
Developmental Stages ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Anthropogenic Factors ◽  
Critical Window ◽  
Hypoxia Inducible Factor 1

In recent years, natural and anthropogenic factors have increased aquatic hypoxia the world over. In most organisms, the cellular response to hypoxia is mediated by the master regulator hypoxia-inducible factor-1 (HIF-1). HIF-1 also plays a critical role in the normal development of the cardiovascular system of vertebrates. We tested the hypothesis that hypoxia exposures which resulted in HIF-1 induction during embryogenesis would be associated with enhanced hypoxia tolerance in subsequent developmental stages. We exposed zebrafish ( Danio rerio ) embryos to just 4 h of severe hypoxia or total anoxia at 18, 24 and 36 h post-fertilization (hpf). Of these, exposure to hypoxia at 24 and 36 hpf as well as anoxia at 36 hpf activated the HIF-1 cellular pathway. Zebrafish embryos that acutely upregulated the HIF-1 pathway had an increased hypoxia tolerance as larvae. The critical window for hypoxia sensitivity and HIF-1 signalling was 24 hpf. Adult male fish had a lower critical oxygen tension ( P crit ) compared with females. Early induction of HIF-1 correlated directly with an increased proportion of males in the population. We conclude that mounting a HIF-1 response during embryogenesis is associated with long-term impacts on the phenotype of later stages which could influence both individual hypoxia tolerance and population dynamics.

scholarly journals Ubiquitination in cancer stem cell: roles and targeted cancer therapy

STEMedicine ◽  
2020 ◽  
Vol 1 (3) ◽  
pp. e37 ◽  
Author(s):  
Liu Liu ◽  
Shasha Yin ◽  
Charles Brobbey ◽  
Wenjian Gan
Keyword(s):  
Signaling Pathways ◽  
Ubiquitin Ligase ◽  
Regulatory Networks ◽  
Critical Role ◽  
Small Subset ◽  
Regulation Of Transcription ◽  
Targeted Cancer Therapy ◽  
Post Translational Modifications ◽  
Proliferation And Differentiation ◽  
Differentiation And Proliferation

Cancer stem cells (CSCs) are a small subset of stem-like cells inside tumors, which possess abilities of unlimited self-renewal, differentiation and proliferation. Extensive studies have suggested that CSCs are one of the major drivers of tumor initiation, metastasis, relapse and therapeutic resistance. Several regulatory networks including transcriptional programs and various signaling pathways tightly control the stemness, proliferation and differentiation of CSCs. Emerging evidence has indicated that post-translational modifications, especially ubiquitination, play a critical role in maintenance of CSC properties. In this review, we summarize current understandings on E3 ubiquitin ligase-mediated regulation of transcription factors and key signaling pathways involved in the regulation of CSCs, and discuss the strategy to target CSCs and E3 ubiquitin ligases for combating cancers.

scholarly journals Cavefish cope with environmental hypoxia by developing more erythrocytes and overexpression of hypoxia inducible genes

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Corine M van der Weele ◽  
William R Jeffery
Keyword(s):  
Normal Development ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Astyanax Mexicanus ◽  
Hypoxia Inducible Factor 1 ◽  
Primitive Hematopoiesis ◽  
Cave Environment ◽  
Surface Dwelling ◽  
Inducible Genes ◽  
Lateral Mesoderm

Dark caves lacking primary productivity can expose subterranean animals to hypoxia. We used the surface-dwelling (surface fish) and cave-dwelling (cavefish) morphs of Astyanax mexicanus as a model for understanding the mechanisms of hypoxia tolerance in the cave environment. Primitive hematopoiesis, which is restricted to the posterior lateral mesoderm in other teleosts, also occurs in the anterior lateral mesoderm in Astyanax, potentially pre-adapting surface fish for hypoxic cave colonization. Cavefish have enlarged both hematopoietic domains and develop more erythrocytes than surface fish, which are required for normal development in both morphs. Laboratory induced hypoxia suppresses growth in surface fish but not in cavefish. Both morphs respond to hypoxia by overexpressing hypoxia-inducible factor 1 (hif1) pathway genes, and some hif1 genes are constitutively upregulated in normoxic cavefish to similar levels as in hypoxic surface fish. We conclude that cavefish cope with hypoxia by increasing erythrocyte development and constitutive hif1 gene overexpression.

A new HIF-1 alpha variant induced by zinc ion suppresses HIF-1-mediated hypoxic responses

2001 ◽  
Vol 114 (22) ◽  
pp. 4051-4061
Author(s):  
Yang-Sook Chun ◽  
Eunjoo Choi ◽  
Eun-Jin Yeo ◽  
Jong Ho Lee ◽  
Myung-Suk Kim ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Consensus Sequence ◽  
Hypoxia Inducible Factor ◽  
Zinc Ion ◽  
Dominant Negative ◽  
Hypoxia Inducible Factor 1 ◽  
Aryl Hydrocarbon ◽  
Hypoxic Conditions ◽  
Alpha Variant ◽  
Inducible Genes

The expressions of hypoxia-inducible genes are upregulated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimer of HIF-1α and HIF-1β/ARNT (aryl hydrocarbon receptor nuclear transporter). Under hypoxic conditions, HIF-1α becomes stabilized and both HIF-1α and ARNT are translocated into the nucleus and codimerized, binding to the HIF-1 consensus sequence and transactivating hypoxia-inducible genes. Other than hypoxia, cobalt and nickel, which can substitute for iron in the ferroprotein, induce the stabilization of HIF-1α and the activation of HIF-1. We found previously that, although zinc, another example of a metal substitute for iron, stabilized HIF-1α, it suppressed the formation of HIF-1 by blocking the nuclear translocation of ARNT. Here, we identify a new spliced variant of human HIF-1α that is induced by zinc. The isoform lacks the 12th exon, which produced a frame-shift and gave a shorter form of HIF-1α (557 amino acids), designated HIF-1αZ (HIF-1α induced by Zn). This moiety was found to inhibit HIF-1 activity and reduce mRNA expressions of the hypoxia-inducible genes. It blocked the nuclear translocation of ARNT but not that of endogenous HIF-1α, and was associated with ARNT in the cytosol. These results suggest that HIF-1αZ functions as a dominant-negative isoform of HIF-1 by sequestering ARNT in the cytosol. In addition, the generation of HIF-1αZ seems to be responsible for the inhibitory effects of the zinc ion on HIF-1-mediated hypoxic responses, because the expressed HIF-1αZ behaved in the same manner as zinc in terms of inhibited HIF-1 activity and ARNT translocation.

scholarly journals Oxygen versus Reactive Oxygen in the Regulation of HIF-1α: The Balance Tips

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Thilo Hagen
Keyword(s):  
Cellular Response ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Thioredoxin Reductase ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Prolyl Hydroxylases ◽  
Hypoxia Inducible Factor 1 ◽  
Transport Chain ◽  
Cellular Oxygen

Hypoxia inducible factor (HIF) is known as the master regulator of the cellular response to hypoxia and is of pivotal importance during development as well as in human disease, particularly in cancer. It is composed of a constitutively expressedβsubunit (HIF-1β) and an oxygen-regulatedαsubunit (HIF-1αand HIF-2α), whose stability is tightly controlled by a family of oxygen- and iron-dependent prolyl hydroxylase enzymes. Whether or not mitochondria-derived reactive oxygen species (ROS) are involved in the regulation of Hypoxia Inducible Factor-1αhas been a matter of contention for the last 10 years, with equally compelling evidence in favor and against their contribution. A number of recent papers appear to tip the balance against a role for ROS. Thus, it has been demonstrated that HIF prolyl hydroxylases are unlikely to be physiological targets of ROS and that the increase in ROS that is associated with downregulation of Thioredoxin Reductase in hypoxia does not affect HIF-1αstabilization. Finally, the protein CHCHD4, which modulates cellular HIF-1αconcentrations by promoting mitochondrial electron transport chain activity, has been proposed to exert its regulatory effect by affecting cellular oxygen availability. These reports are consistent with the hypothesis that mitochondria play a critical role in the regulation of HIF-1αby controlling intracellular oxygen concentrations.

Matriptase-2 (TMPRSS6) is directly up-regulated by hypoxia inducible factor-1: identification of a hypoxia-responsive element in the TMPRSS6 promoter region

2012 ◽  
Vol 393 (6) ◽  
pp. 535-540 ◽  
Author(s):  
Eva Maurer ◽  
Michael Gütschow ◽  
Marit Stirnberg
Keyword(s):  
Promoter Region ◽  
Iron Homeostasis ◽  
Hypoxia Inducible Factor ◽  
Type Ii ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Hypoxia Responsive Element ◽  
Responsive Element ◽  
Main Regulator ◽  
Transmembrane Serine Protease

Abstract The type II transmembrane serine protease matriptase-2 (TMPRSS6) down-regulates the expression of hepcidin, the main regulator of systemic iron homeostasis, and increases in this way iron plasma levels. Matriptase-2 is up-regulated under hypoxic conditions, providing a new link between hypoxia signaling and iron homeostasis. In this study, we have characterized the TMPRSS6 promoter region and identified a functional hypoxia-responsive element (HRE). Mutations of the hypoxia inducible factor (HIF)-binding site located within the HRE abrogate HIF-1α-dependent induction of TMPRSS6 expression. The action of HIF-1α on TMPRSS6 promoter activity reveals a new regulative element for the suppression of hepcidin synthesis.

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