scholarly journals Hif1α-Dependent Hypoxia Signaling Contributes to the Survival of Deep-Layer Neurons and Cortex Formation in A Mouse Model

2021 ◽  
Author(s):  
Daisuke Sakai ◽  
Takeru Sugawara ◽  
Tomonori Kurokawa ◽  
Yuki Murakami ◽  
Mitsuhiro Tomosugi ◽  
...  
Keyword(s):  
Brain Development ◽  
Knockout Mice ◽  
Deep Layer ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Vegf Signaling ◽  
Hypoxia Inducible Factor 1 ◽  
Downstream Effector ◽  
Abnormal Head ◽  
Hypoxia Signaling

Abstract Hypoxia-inducible factor 1 a (Hif1α) plays a crucial role in brain development. To study the function of Hif1α in early brain development, we generated neuroepithelial cell-specific Hif1α-knockout mice. Hif1α-knockout mice died soon after birth; these mice exhibited an abnormal head shape, indicating the presence of brain defects. Morphological analysis revealed that Hif1α ablation reduced the overall size of the brain, especially affecting the telencephalon. Neuronal apoptosis predominantly occurred in deep-layer neurons, consequently the alignment of cortical layers was severely disorganized in Hif1α knockout mice. Furthermore, we demonstrated that Vegf signaling contributes to the survival of deep-layer neurons as a downstream effector of Hif1α-dependent hypoxia signaling. Taken together, our findings demonstrate that Hif1α plays a critical role in the early stages of telencephalon development.

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 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.

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 Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha

Oncotarget ◽  
2017 ◽  
Vol 8 (34) ◽  
pp. 56110-56125 ◽  
Author(s):  
Chao Zhang ◽  
Chunzhang Yang ◽  
Michael J. Feldman ◽  
Herui Wang ◽  
Ying Pang ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxia Signaling

370 Hypoxic Conditions and Hypoxia-Inducible Factor 1-Alpha are Critical in the Radioresistance of Meningioma

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 286-287
Author(s):  
Michael Karsy ◽  
David Gillespie ◽  
Randy L Jensen
Keyword(s):  
Cell Viability ◽  
Cell Density ◽  
Cell Lines ◽  
Oxygen Tension ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Fractionated Radiotherapy ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Meningioma Cell

Abstract INTRODUCTION Meningiomas are common benign intracranial neoplasms treated with a combination of surgical resection, radiotherapy, and chemotherapy. Hypoxia-inducible factor 1 alpha (HIF1A) can predict disease aggressiveness, response to oxygen tension and regulate meningioma pathogenesis. The role of HIF1A and hypoxia was explored in the radiation resistance of meningioma, hypothesizing that HIF1A confers resistance to radiotherapy in meningiomas and that oxygen tension is key to radiation responsiveness. METHODS Various primary meningioma cell lines were studied (IOMM-LE, JEN, GAR, SAM). GAR primary cell lines were utilized in addition to a shRNA-HIF1A knockdown (GAR1589). Cell proliferation, viability, and apoptosis were evaluated in response to radiation in both normoxia (21% O2) and hypoxia (1% O2). RESULTS >Doubling times of the various meningioma cell lines ranged from 19.5 to 213.2 hours. Cell density impacted responsiveness to radiation, with confluent cells showing greater dose tolerance before reduced proliferation. In normoxic environments, HIF1A knockout resulted in increased susceptibility to single radiation fractions of 2 Gy (P = 0.05) and 10 Gy (P = 0.02); however, both cells had strong susceptibility at 20 Gy. Hypoxic environments reduced the viability differences between GAR and GAR1589 cells and slightly increased GAR cell viability at 2 Gy (P < 0.05). Fractionated radiotherapy (2 Gy) daily showed reduced GAR and GAR1589 cell viability in normoxia and hypoxia. Cell viability for GAR1589 at 3 fractions of 2-Gy radiation was reduced, but this effect was eliminated in hypoxic environments. Apoptosis was increased in GAR1589 cells at baseline and with increased fractions of radiation; however, this effect was reduced in hypoxic conditions. CONCLUSION These results support important findings for meningioma response to radiation, including 1) importance of cell density, 2) dependence on HIF1A mutation, and 3) a critical role for oxygen tension. These results may be helpful in understanding the mechanisms of meningioma resistance to radiation and serve as a model to trial novel adjuvant therapies and treatment types.

scholarly journals Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment

2018 ◽  
Vol 115 (41) ◽  
pp. E9640-E9648 ◽  
Author(s):  
Jie Lan ◽  
Haiquan Lu ◽  
Debangshu Samanta ◽  
Shaima Salman ◽  
You Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Adenosine Receptor ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Hypoxia Inducible Factor 1

Breast cancer stem cells (BCSCs), which are characterized by a capacity for unlimited self-renewal and for generation of the bulk cancer cell population, play a critical role in cancer relapse and metastasis. Hypoxia is a common feature of the cancer microenvironment that stimulates the specification and maintenance of BCSCs. In this study, we found that hypoxia increased expression of adenosine receptor 2B (A2BR) in human breast cancer cells through the transcriptional activity of hypoxia-inducible factor 1. The binding of adenosine to A2BR promoted BCSC enrichment by activating protein kinase C-δ, which phosphorylated and activated the transcription factor STAT3, leading to increased expression of interleukin 6 and NANOG, two key mediators of the BCSC phenotype. Genetic or pharmacological inhibition of A2BR expression or activity decreased hypoxia- or adenosine-induced BCSC enrichment in vitro, and dramatically impaired tumor initiation and lung metastasis after implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice. These data provide evidence that targeting A2BR might be an effective strategy to eradicate BCSCs.

scholarly journals The regulation of Hypoxia-Inducible Factor-1 (HIF-1alpha) expression by Protein Disulfide Isomerase (PDI)

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246531
Author(s):  
Yukino Kobayashi ◽  
Ami Oguro ◽  
Yuta Hirata ◽  
Susumu Imaoka
Keyword(s):  
Cancer Progression ◽  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Redox State ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Disulfide Isomerase ◽  
Hypoxia Inducible Factor 1 ◽  
Protein Disulfide

Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor, plays a critical role in adaption to hypoxia, which is a major feature of diseases, including cancer. Protein disulfide isomerase (PDI) is up-regulated in numerous cancers and leads to cancer progression. PDI, a member of the TRX superfamily, regulates the transcriptional activities of several transcription factors. To investigate the mechanisms by which PDI affects the function of HIF-1alpha, the overexpression or knockdown of PDI was performed. The overexpression of PDI decreased HIF-1alpha expression in the human hepatocarcinoma cell line, Hep3B, whereas the knockdown of endogenous PDI increased its expression. NH4Cl inhibited the decrease in HIF-1alpha expression by PDI overexpression, suggesting that HIF-1alpha was degraded by the lysosomal pathway. HIF-1alpha is transferred to lysosomal membranes by heat shock cognate 70 kDa protein (HSC70). The knockdown of HSC70 abolished the decrease, and PDI facilitated the interaction between HIF-1alpha and HSC70. HIF-1alpha directly interacted with PDI. PDI exists not only in the endoplasmic reticulum (ER), but also in the cytosol. Hypoxia increased cytosolic PDI. We also investigated changes in the redox state of HIF-1alpha using PEG-maleimide, which binds to thiols synthesized from disulfide bonds by reduction. An up-shift in the HIF-1alpha band by the overexpression of PDI was detected, suggesting that PDI formed disulfide bond in HIF-1alpha. HIF-1alpha oxidized by PDI was not degraded in HSC70-knockdown cells, indicating that the formation of disulfide bond in HIF-1alpha was important for decreases in HIF-1alpha expression. To the best of our knowledge, this is the first study to show the regulation of the expression and redox state of HIF-1alpha by PDI. We also demonstrated that PDI formed disulfide bonds in HIF-1alpha 1–245 aa and decreased its expression. In conclusion, the present results showed that PDI is a novel factor regulating HIF-1alpha through lysosome-dependent degradation by changes in its redox state.

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