Publications

Analysis of Hypoxia‐Inducible Factor 1α Expression and its Effects on Invasion and Metastasis

Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs

BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca(2+)]i in PASMCs, promoting CHPH pathogenesis.

Induction of hypoxia‐inducible factor‐1 (HIF‐1) and its target genes following focal ischaemia in rat brain

Abstract HIF‐1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF‐1α and HIF‐1β protein subunits. It binds to promoter/enhancer elements and stimulates the transcription of hypoxia‐inducible target genes, including glucose transporter‐1 and the glycolytic enzymes. Because HIF‐1 activation might promote cell survival in hypoxic tissues, we studied the effect of permanent middle cerebral artery occlusion on the expression of HIF‐1α, HIF‐1β and several HIF‐1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF‐1α, glucose transporter‐1 and several glycolytic enzymes were up‐regulated in the peri‐infarct penumbra. This was observed by 7.5 h after the onset of ischaemia and increased further at 19 and 24 h. Regional cerebral blood flow was moderately decreased at 1 and 24 h after the ischaemia in areas of HIF‐1 and HIF‐1 target gene induction. Because hypoxia induces HIF‐1 in other tissues, systemic hypoxia (6% O 2 for 4.5 h) was also shown to increase HIF‐1α protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF‐1 and its target genes. This is the first study to show induction of HIF‐1 after focal ischaemia in brain. Increased expression of HIF‐1 target genes as a result of HIF‐1 activation by hypoxia may contribute to tissue viability in the hypoxic/ischaemic penumbra by increasing glucose transport and glycolysis.

An Xba I polymorphism 3′ to the human erythropoietin (EPO) gene

Journal Article An Xba I polymorphism 3′ to the human erythropoietin (EPO) gene Get access Gregg L. Semenza, Gregg L. Semenza Genetics Unit, Department of Pediatrics, Johns Hopkins School of MedicineBaltimore, MD 21205, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar John A. A. Ladias, John A. A. Ladias Genetics Unit, Department of Pediatrics, Johns Hopkins School of MedicineBaltimore, MD 21205, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Stylianos E. Antonarakis Stylianos E. Antonarakis Genetics Unit, Department of Pediatrics, Johns Hopkins School of MedicineBaltimore, MD 21205, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 15, Issue 16, 25 August 1987, Page 6768, https://doi.org/10.1093/nar/15.16.6768 Published: 25 August 1987

Supplementary Fig. S1 from Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity

Supplementary Fig. S1 from Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity

HIF-1, O2, and the 3 PHDs

Pharmacologic HIF stabilization activates costimulatory receptor expression to increase antitumor efficacy of adoptive T cell therapy

Adoptive cell transfer (ACT) is a therapeutic strategy to augment antitumor immunity. Here, we report that ex vivo treatment of mouse CD8 + T cells with dimethyloxalylglycine (DMOG), a stabilizer of hypoxia-inducible factors (HIFs), induced HIF binding to the genes encoding the costimulatory receptors CD81, GITR, OX40, and 4-1BB, leading to increased expression. DMOG treatment increased T cell killing of melanoma cells, which was further augmented by agonist antibodies targeting each costimulatory receptor. In tumor-bearing mice, ACT using T cells treated ex vivo with DMOG and agonist antibodies resulted in decreased tumor growth compared to ACT using control T cells and increased intratumoral markers of CD8 + T cells (CD7, CD8A, and CD8B1), natural killer cells (NCR1 and KLRK1), and cytolytic activity (perforin-1 and tumor necrosis factor–α). Costimulatory receptor gene expression was also induced when CD8 + T cells were treated with three highly selective HIF stabilizers that are currently in clinical use.

HIF-1 Inhibitors for Cancer Therapy: From Gene Expression to Drug Discovery

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric protein composed of HIF-1alpha and HIF-1alpha subunits, which is activated in response to reduced O2 availability. HIF-1 transactivates genes encoding proteins that are involved in key aspects of the cancer phenotype, including cell immortalization and de-differentiation, stem cell maintenance, genetic instability, glucose uptake and metabolism, pH regulation, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. Increased HIF-1alpha levels, as determined by immunohistochemical analysis of tumor biopsy specimens, is associated with increased mortality in many human cancers. Drugs that inhibit HIF-1 activity and have anti-cancer effects in vivo have been identified and clinical trials are warranted to establish the contexts in which addition of such agents to therapy protocols will result in increased patient survival.

HIF-lα als Regulator von Tumorangiogenese, Gefäßmorphologie und Wachstum des Adenokarzinoms des Magens

Cellular and Molecular Dissection of Reperfusion Injury

Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

Following an investigation by the University of the Ryukyus, which revealed that figures that appeared within this paper had also been used in other papers without appropriate attribution or explanation (a pattern repeated over a number of publications in different journals), the Editorial Board of the Biochemical Journal retract this paper. The last author, Naoki Mori, takes full responsibility for the misrepresentation of data in this paper.

Chairman’s Summary: Mechanisms of Oxygen Homeostasis, Circa 1999

A Nuclear Factor Induced by Hypoxia via De Novo Protein Synthesis Binds to the Human Erythropoietin Gene Enhancer at a Site Required for Transcriptional Activation

We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.

Extra-Hematopoietic Action of Erythropoietin

Hypoxia-inducible factor 1: Regulator of mitochondrial metabolism and mediator of ischemic preconditioning

Regulation of Ischemia-Induced Vascularization by Hypoxia-Inducible Factor 1

Effect of Protein Kinase and Phosphatase Inhibitors on Expression of Hypoxia Inducible Factor 1

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric bHLH-PAS protein essential for erythropoietin gene transcription in hypoxic cells. Here we show that both 2-aminopurine and sodium fluoride, inhibitors of serine/threonine kinases and phosphatases, respectively, interfered with the hypoxic induction of HIF-1 DNA-binding activity and expression of HIF-1 alpha and HIF-1 beta(ARNT) subunits. Genistein, an inhibitor of tyrosine kinases, completely blocked the synthesis of both HIF-1 subunits as well as HIF-1 DNA-binding activity. Sodium orthovanadate, an inhibitor of tyrosine phosphatases increased the basal level of HIF-1 proteins and HIF-1 activity. These data suggest that protein phosphorylation events play an important role in the hypoxia signal-transduction pathway that leads to synthesis of HIF-1 alpha and HIF-1 beta proteins and the induction of HIF-1 DNA-binding activity.

Oxygen sensing in the body

Data from Hypoxia Selectively Enhances Integrin α<sub>5</sub>β<sub>1</sub> Receptor Expression in Breast Cancer to Promote Metastasis

<div>Abstract<p>Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1α, but not HIF-2α, for hypoxic induction in breast cancer cells. ITGA5 (α<sub>5</sub> subunit) is required for metastasis to lymph nodes and lungs in breast cancer models, and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality.</p><p><b>Implications:</b> These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors. <i>Mol Cancer Res; 15(6); 723–34. ©2017 AACR</i>.</p></div>