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Gregg L Semenza - One of the best experts on this subject based on the ideXlab platform.

  • Hypoxia-Inducible Factor 1 and Cardiovascular Disease
    Annual review of physiology, 2013
    Co-Authors: Gregg L Semenza
    Abstract:

    Cardiac function is required for blood circulation and systemic oxygen delivery. However, the heart has intrinsic oxygen demands that must be met to maintain effective contractility. Hypoxia-Inducible Factor 1 (HIF-1) is a transcription Factor that functions as a master regulator of oxygen homeostasis in all metazoan species. HIF-1 controls oxygen delivery, by regulating angiogenesis and vascular remodeling, and oxygen utilization, by regulating glucose metabolism and redox homeostasis. Analysis of animal models suggests that by activation of these homeostatic mechanisms, HIF-1 plays a critical protective role in the pathophysiology of ischemic heart disease and pressure-overload heart failure.

  • Activation of Hypoxia-Inducible Factor-1 in pulmonary arterial smooth muscle cells by endothelin-1.
    American journal of physiology. Lung cellular and molecular physiology, 2013
    Co-Authors: Sarah Pisarcik, Gregg L Semenza, Julie Maylor, Xin Yun, Clark Undem, J. T. Sylvester, Larissa A. Shimoda
    Abstract:

    Numerous cellular responses to hypoxia are mediated by the transcription Factor Hypoxia-Inducible Factor-1 (HIF-1). HIF-1 plays a central role in the pathogenesis of hypoxic pulmonary hypertension....

  • pyruvate kinase m2 is a phd3 stimulated coactivator for hypoxia inducible Factor 1
    Cell, 2011
    Co-Authors: Hongxia Hu, Ryan Chang, Jun Zhong, Matthew K Knabel, Robert N Omeally, Robert N Cole, Akhilesh Pandey, Gregg L Semenza
    Abstract:

    The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by Hypoxia-Inducible Factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O2 consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells.

  • Hypoxia-Inducible Factor-1-dependent mechanisms of vascularization and vascular remodelling.
    Cardiovascular research, 2010
    Co-Authors: Sergio Rey, Gregg L Semenza
    Abstract:

    The vascular system delivers oxygen and nutrients to every cell in the vertebrate organism. Hypoxia-Inducible Factor 1 (HIF-1) is a master regulator of hypoxic/ischaemic vascular responses, driving transcriptional activation of hundreds of genes involved in vascular reactivity, angiogenesis, arteriogenesis, and the mobilization and homing of bone marrow-derived angiogenic cells. This review will focus on the pivotal role of HIF-1 in vascular homeostasis, the involvement of HIF-1 in vascular diseases, and recent advances in targeting HIF-1 for therapy in preclinical models.

  • defining the role of hypoxia inducible Factor 1 in cancer biology and therapeutics
    Oncogene, 2010
    Co-Authors: Gregg L Semenza
    Abstract:

    Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared to normal tissue and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by Hypoxia-Inducible Factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (i) clinical data associating increased HIF-1 levels with patient mortality; (ii) preclinical data linking HIF-1 activity with tumor growth; (iii) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology; and (iv) pharmacological data demonstrating anti-cancer effects of HIF-1 inhibitors in mouse models of human cancer.

Kiichi Hirota - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of angiogenesis by Hypoxia-Inducible Factor 1
    Critical reviews in oncology hematology, 2006
    Co-Authors: Kiichi Hirota, Gregg L Semenza
    Abstract:

    Hypoxia is an imbalance between oxygen supply and demand that occurs in cancer and in ischemic cardiovascular disease. Hypoxia-Inducible Factor 1 (HIF-1) was originally identified as the transcription Factor that mediates hypoxia-induced erythropoietin expression. More recently, the delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF-1 in the regulation of angiogenic growth Factors. In this review, we discuss the role of HIF-1 in developmental, adaptive and pathological angiogenesis. In addition, potential therapeutic interventions involving modulation of HIF-1 activity in ischemic cardiovascular disease and cancer will be discussed.

  • Activation of Hypoxia-Inducible Factor 1 during macrophage differentiation
    American journal of physiology. Cell physiology, 2006
    Co-Authors: Tomoyuki Oda, Kiichi Hirota, Kenichiro Nishi, Satoshi Takabuchi, Seiko Oda, Hiroko Yamada, Toshiyuki Arai, Kazuhiko Fukuda, Toru Kita, Takehiko Adachi
    Abstract:

    Monocytes/macrophages of the myeloid lineage are the main cellular effectors of innate immunity. Hypoxia-Inducible Factor 1 (HIF-1) is essential for myeloid cell activation in response to inflammat...

  • Regulation of Hypoxia-Inducible Factor 1 by prolyl and asparaginyl hydroxylases.
    Biochemical and biophysical research communications, 2005
    Co-Authors: Kiichi Hirota, Gregg L Semenza
    Abstract:

    Hypoxia-Inducible Factor 1 (HIF-1) functions as a master regulator of oxygen homeostasis by mediating a wide range of cellular and systemic adaptive physiological responses to reduced oxygen availability. In this review, we will summarize recent progress in elucidating the molecular mechanisms of HIF-1 activation, focusing on the role of oxygen-dependent prolyl and asparaginyl hydroxylases in hypoxia signal transduction.

  • Rac1 Activity Is Required for the Activation of Hypoxia-Inducible Factor 1
    The Journal of biological chemistry, 2001
    Co-Authors: Kiichi Hirota, Gregg L Semenza
    Abstract:

    Abstract Hypoxia-Inducible Factor 1 (HIF-1) is a transcription Factor that mediates cellular and systemic homeostatic responses (including erythropoiesis, angiogenesis, and glycolysis) to reduced O2 availability in mammals. Hypoxia induces both the protein expression and transcriptional activity of the HIF-1α subunit. However, the molecular mechanisms of sensing and signal transduction by which changes in O2 concentration result in changes in HIF-1 activity are poorly understood. We report here that the small GTPase Rac1 is activated in response to hypoxia and is required for the induction of HIF-1α protein expression and transcriptional activity in hypoxic cells.

Peng Gao - One of the best experts on this subject based on the ideXlab platform.

  • High-throughput screening identifies CHMP4A associated with Hypoxia-Inducible Factor 1.
    Life sciences, 2010
    Co-Authors: Taiping Shi, Yunqiao Dong, Peng Gao
    Abstract:

    Tumor hypoxia is a common phenomenon and Hypoxia-Inducible Factor-1 is the transcription Factor that is most closely associated with hypoxia. Hypoxia-Inducible Factor-1 is overexpressed in most solid tumors and plays a vital role in hypoxic acclimatization, energy metabolism, tumor angiogenesis, tumor invasion, and drug tolerance in cancer cells. We aimed to identify novel human genes associated with the stability and transcriptional activity of Hypoxia-Inducible Factor-1. A cell-based dual luciferase reporter system based on a hypoxia responsive element luciferase reporter gene was constructed to screen 409 novel human genes cloned in our lab. Western blot analysis was used to examine the changes in the expression level of Hypoxia-Inducible Factor-1 α, and RT-PCR analysis was used to detect the transcription level of adenylate kinase 3. Our results demonstrated that chromatin-modifying protein 4A could significantly up-regulate the hypoxia responsive element luciferase activity under both normoxic and cobalt chloride-induced hypoxic environment in HeLa cells. Moreover, Chromatin-modifying protein 4A could increase the expression of Hypoxia-Inducible Factor-1 α protein under normoxic condition, and enhance the transcription level of adenylate kinase 3, which is one of the target genes of Hypoxia-Inducible Factor-1. The functional screening platform therefore can be applied for the high-throughput screening of Hypoxia-Inducible Factor-1-related genes, which would provide new insights into underlying molecular mechanisms that may regulate hypoxia in mammalian cells. Copyright © 2010 Elsevier Inc. All rights reserved.

  • High-throughput screening identifies CHMP4A associated with Hypoxia-Inducible Factor 1.
    Life Sciences, 2010
    Co-Authors: Taiping Shi, Yunqiao Dong, Peng Gao
    Abstract:

    Abstract Aims Tumor hypoxia is a common phenomenon and Hypoxia-Inducible Factor-1 is the transcription Factor that is most closely associated with hypoxia. Hypoxia–inducible Factor–1 is overexpressed in most solid tumors and plays a vital role in hypoxic acclimatization, energy metabolism, tumor angiogenesis, tumor invasion, and drug tolerance in cancer cells. We aimed to identify novel human genes associated with the stability and transcriptional activity of hypoxia–inducible Factor–1. Main methods A cell-based dual luciferase reporter system based on a hypoxia responsive element luciferase reporter gene was constructed to screen 409 novel human genes cloned in our lab. Western blot analysis was used to examine the changes in the expression level of hypoxia–inducible Factor–1 α, and RT-PCR analysis was used to detect the transcription level of adenylate kinase 3. Key findings Our results demonstrated that chromatin-modifying protein 4A could significantly up-regulate the hypoxia responsive element luciferase activity under both normoxic and cobalt chloride-induced hypoxic environment in HeLa cells. Moreover, Chromatin–modifying protein 4A could increase the expression of hypoxia–inducible Factor–1 α protein under normoxic condition, and enhance the transcription level of adenylate kinase 3, which is one of the target genes of hypoxia–inducible Factor–1. Significance The functional screening platform therefore can be applied for the high-throughput screening of hypoxia–inducible Factor–1-related genes, which would provide new insights into underlying molecular mechanisms that may regulate hypoxia in mammalian cells.

Wei-gang Fang - One of the best experts on this subject based on the ideXlab platform.

  • Hypoxia-Inducible Factor-1 in tumour angiogenesis.
    World journal of gastroenterology, 2004
    Co-Authors: Yong-hong Shi, Wei-gang Fang
    Abstract:

    Hypoxia-Inducible Factor-1 (HIF-1), composed of HIF-α and HIF-β subunits, is a heterodimeric transcriptional activator. In response to hypoxia, stimulation of growth Factors, and activation of oncogenes as well as carcinogens, HIF-1α is overexpressed and/or activated and targets those genes which are required for angiogenesis, metabolic adaptation to low oxygen and promotes survival. HIF-1 is critical for both physiological and pathological processes. Several dozens of putative direct HIF-1 target genes have been identified on the basis of one or more cis-acting hypoxia-response elements that contain an HIF-1 binding site. A variety of regulators including growth Factors, genetic alterations, stress activators, and some carcinogens have been documented for regulation of HIF-1 in which several signaling pathways are involved depending on the stimuli and cell types. Activation of HIF-1 in combination with activated signaling pathways and regulators is implicated in tumour progression and prognosis. This review presents a summary of the structure and function of HIF-1α, and correlation among specific regulators and their signaling pathways.

Sun Ziqin - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of Transcriptional Activity of Hypoxia-Inducible Factor 1
    Journal of Medical Molecular Biology, 2005
    Co-Authors: Sun Ziqin
    Abstract:

    Hypoxia-Inducible Factor 1 (HIF-1) is a master regulator of oxygen homeostasis induced by hypoxia, and it plays a critical role in controlling oxygen delivery and metabolic adaptation of tumor cells to hypoxic conditions.Although HIF-1 is a heterodimer composed of a and β subunits, only HIF-1 a is regulated by oxygen tension and the regulation of HIF-1α occurs at post-trans-lational level, involving modifications of hydroxylation, acetylation and phosphorylation.In addition, it was discovered that phosphatidylinositol 3-kinase/Akt pathway is involved in the HIF-1 trans-activation.The study of HIF-1 regulation will help us to get an insight into the molecular mechanisms responsible for the adaptation of tumor cells to hypoxia.