Transcriptional regulation by hypoxia inducible factors

Abstract The cellular response to oxygen deprivation is governed largely by a family of transcription factors known as Hypoxia Inducible Factors (HIFs). This review focuses on the molecular mechanisms by which HIFs regulate the transcriptional apparatus to enable the cellular and organismal response to hypoxia. We discuss here how the various HIF polypeptides, their posttranslational modifications, binding partners and transcriptional cofactors affect RNA polymerase II activity to drive context-dependent transcriptional programs during hypoxia.

[1]  M. Fortini,et al.  Notch signaling: the core pathway and its posttranslational regulation. , 2009, Developmental cell.

[2]  M. Gassmann,et al.  Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. , 1998, Genes & development.

[3]  Wilhelm Krek,et al.  Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. , 2012, Genes & development.

[4]  L. Wartman,et al.  Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. , 1998, Gene expression.

[5]  Andreas Gocht,et al.  The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. , 2005, Cellular signalling.

[6]  J. Dulak,et al.  HIF-1: the knowns and unknowns of hypoxia sensing. , 2004, Acta biochimica Polonica.

[7]  Y Fujii-Kuriyama,et al.  A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Junjie Chen,et al.  Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. , 2010, Molecular cell.

[9]  Jeong Hoon Kim,et al.  Role of the Coiled-coil Coactivator (CoCoA) in Aryl Hydrocarbon Receptor-mediated Transcription* , 2004, Journal of Biological Chemistry.

[10]  A. Harris,et al.  Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor* , 2004, Journal of Biological Chemistry.

[11]  Jiannis Ragoussis,et al.  High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. , 2011, Blood.

[12]  L. Kasper,et al.  Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases , 2010, Epigenetics.

[13]  I. Yasinska,et al.  S‐nitrosation of Cys‐800 of HIF‐1α protein activates its interaction with p300 and stimulates its transcriptional activity , 2003, FEBS letters.

[14]  P. Ratcliffe,et al.  Oxygen-regulated and Transactivating Domains in Endothelial PAS Protein 1: Comparison with Hypoxia-inducible Factor-1α* , 1999, The Journal of Biological Chemistry.

[15]  G. Semenza,et al.  Dimerization, DNA Binding, and Transactivation Properties of Hypoxia-inducible Factor 1* , 1996, The Journal of Biological Chemistry.

[16]  M. Krstic-Demonacos,et al.  PCAF is an HIF-1α cofactor that regulates p53 transcriptional activity in hypoxia , 2008, Oncogene.

[17]  Y. Miyagi,et al.  HIF2a-Sp1 interaction mediates a deacetylation-dependent FVII-gene activation under hypoxic conditions in ovarian cancer cells , 2012 .

[18]  Brian Keith,et al.  HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. , 2006, Genes & development.

[19]  D. Peet,et al.  FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. , 2002, Genes & development.

[20]  K. Eckardt,et al.  The specific contribution of hypoxia-inducible factor-2alpha to hypoxic gene expression in vitro is limited and modulated by cell type-specific and exogenous factors. , 2008, Experimental cell research.

[21]  G. Powis,et al.  HIF-1 regulation: not so easy come, easy go. , 2008, Trends in biochemical sciences.

[22]  D. Peet,et al.  Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch , 2002, Science.

[23]  J. Pouysségur,et al.  p42/p44 Mitogen-activated Protein Kinases Phosphorylate Hypoxia-inducible Factor 1α (HIF-1α) and Enhance the Transcriptional Activity of HIF-1* , 1999, The Journal of Biological Chemistry.

[24]  Kou-Juey Wu,et al.  Direct regulation of TWIST by HIF-1α promotes metastasis , 2008, Nature Cell Biology.

[25]  Helen C. Hurst,et al.  Physical and Functional Interactions among AP-2 Transcription Factors, p300/CREB-binding Protein, and CITED2* , 2003, The Journal of Biological Chemistry.

[26]  S. Olechnowicz,et al.  Hypoxic Induction of the Regulator of G-Protein Signalling 4 Gene Is Mediated by the Hypoxia-Inducible Factor Pathway , 2012, PloS one.

[27]  Yuichi Makino,et al.  Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression , 2001, Nature.

[28]  Y. Fujii‐Kuriyama,et al.  The Transcriptional Activation Function of the HIF-like Factor Requires Phosphorylation at a Conserved Threonine* , 2002, Journal of Biological Chemistry.

[29]  L. Poellinger,et al.  Functional analysis of hypoxia-inducible factor-1 alpha-mediated transactivation. Identification of amino acid residues critical for transcriptional activation and/or interaction with CREB-binding protein. , 2002, The Journal of biological chemistry.

[30]  J. W. Davis,et al.  Identification of the CREB-binding Protein/p300-interacting Protein CITED2 as a Peroxisome Proliferator-activated Receptor α Coregulator* , 2004, Journal of Biological Chemistry.

[31]  R. Cole,et al.  RACK1 Competes with HSP90 for Binding to HIF-1α and is Required for O2-independent and HSP90 Inhibitor-induced Degradation of HIF-1α , 2007 .

[32]  K. G. Guruharsha,et al.  The Notch signalling system: recent insights into the complexity of a conserved pathway , 2012, Nature Reviews Genetics.

[33]  P. Ratcliffe,et al.  Independent function of two destruction domains in hypoxia‐inducible factor‐α chains activated by prolyl hydroxylation , 2001, The EMBO journal.

[34]  F. Grosveld,et al.  Hypoxia Inducible Factor 3α Plays a Critical Role in Alveolarization and Distal Epithelial Cell Differentiation during Mouse Lung Development , 2013, PloS one.

[35]  D. Qian,et al.  HIF1α Protein Stability Is Increased by Acetylation at Lysine 709* , 2012, The Journal of Biological Chemistry.

[36]  W. Ijcken,et al.  Erratum: Hypoxia inducible factor 3α plays a critical role in alveolarization and distal epithelial cell differentiation during mouse lung development (The PLOS ONE Staff (2013) 8:2 (e57695) DOI: 10.1371/journal.pone.0057695) , 2015 .

[37]  U. Lendahl,et al.  Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways , 2008, Proceedings of the National Academy of Sciences.

[38]  J. Cleveland,et al.  Two transactivation mechanisms cooperate for the bulk of HIF‐1‐responsive gene expression , 2005, The EMBO journal.

[39]  Xiuping Liu,et al.  The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. , 2011, Cancer research.

[40]  M. Ivan,et al.  Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein , 2000, Nature Cell Biology.

[41]  Quynh-Thu Le,et al.  Lysyl oxidase is essential for hypoxia-induced metastasis , 2006, Nature.

[42]  Brian Keith,et al.  Hypoxia-Inducible Factors, Stem Cells, and Cancer , 2007, Cell.

[43]  P. W. Conrad,et al.  EPAS1 trans-Activation during Hypoxia Requires p42/p44 MAPK* , 1999, The Journal of Biological Chemistry.

[44]  P. Ratcliffe,et al.  Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia-inducible factor (FIH) activity. , 2004, The Biochemical journal.

[45]  Daniel J. Peet,et al.  Cell-specific Regulation of Hypoxia-inducible Factor (HIF)-1α and HIF-2α Stabilization and Transactivation in a Graded Oxygen Environment* , 2006, Journal of Biological Chemistry.

[46]  Orian S. Shirihai,et al.  The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α , 2010, Cell.

[47]  M. Simon,et al.  The N-Terminal Transactivation Domain Confers Target Gene Specificity of Hypoxia-inducible Factors HIF-1α and HIF-2α , 2007 .

[48]  J. Pouysségur,et al.  The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. , 2006, Cancer research.

[49]  U. Lendahl,et al.  Hypoxia requires notch signaling to maintain the undifferentiated cell state. , 2005, Developmental cell.

[50]  K. Kivirikko,et al.  Catalytic Properties of the Asparaginyl Hydroxylase (FIH) in the Oxygen Sensing Pathway Are Distinct from Those of Its Prolyl 4-Hydroxylases* , 2004, Journal of Biological Chemistry.

[51]  R. Conaway,et al.  Multiple Splice Variants of the Human HIF-3α Locus Are Targets of the von Hippel-Lindau E3 Ubiquitin Ligase Complex* , 2003, The Journal of Biological Chemistry.

[52]  K. Kivirikko,et al.  Hypoxia-inducible factor (HIF)-3alpha is subject to extensive alternative splicing in human tissues and cancer cells and is regulated by HIF-1 but not HIF-2. , 2010, The international journal of biochemistry & cell biology.

[53]  Y. Fujii‐Kuriyama,et al.  Molecular mechanisms of transcription activation by HLF and HIF1α in response to hypoxia: their stabilization and redox signal‐induced interaction with CBP/p300 , 1999, The EMBO journal.

[54]  Nan Tang,et al.  Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis , 2004 .

[55]  Yukihiro Kondo,et al.  Expression and Characterization of Hypoxia-Inducible Factor (HIF)-3α in Human Kidney: Suppression of HIF-Mediated Gene Expression by HIF-3α , 2001 .

[56]  Jing Chen,et al.  Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth , 2009, Science Signaling.

[57]  P. Carmeliet,et al.  Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis , 1998, Nature.

[58]  S. Bhattacharya,et al.  An essential role for p300/CBP in the cellular response to hypoxia. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[59]  A. Kung,et al.  Preferential binding of HIF-1 to transcriptionally active loci determines cell-type specific response to hypoxia , 2009, Genome Biology.

[60]  R. Hammer,et al.  The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. , 1998, Genes & development.

[61]  Hee June Choi,et al.  Negative regulation of hypoxic responses via induced Reptin methylation. , 2010, Molecular cell.

[62]  M. Raes,et al.  Intermittent hypoxia changes HIF-1α phosphorylation pattern in endothelial cells: Unravelling of a new PKA-dependent regulation of HIF-1α , 2007 .

[63]  G. Semenza,et al.  Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 , 2011, Cell.

[64]  Trevor Hastie,et al.  Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers , 2006, PLoS medicine.

[65]  R. Evjenth,et al.  Interaction between HIF‐1α (ODD) and hARD1 does not induce acetylation and destabilization of HIF‐1α , 2005 .

[66]  G. Powis,et al.  Hypoxia-Associated Factor, a Novel E3-Ubiquitin Ligase, Binds and Ubiquitinates Hypoxia-Inducible Factor 1α, Leading to Its Oxygen-Independent Degradation , 2008, Molecular and Cellular Biology.

[67]  W. Houry,et al.  Rvb1-Rvb2: essential ATP-dependent helicases for critical complexes. , 2010, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[68]  The meaning of pausing. , 2010, Molecular cell.

[69]  Cheng-Jun Hu,et al.  Upstream Stimulatory Factor 2 and Hypoxia-Inducible Factor 2α (HIF2α) Cooperatively Activate HIF2 Target Genes during Hypoxia , 2012, Molecular and Cellular Biology.

[70]  O. Hankinson,et al.  Cloning of a factor required for activity of the Ah (dioxin) receptor. , 1991, Science.

[71]  H. Esumi,et al.  Identification of Hypoxia-inducible Factor 1 Ancillary Sequence and Its Function in Vascular Endothelial Growth Factor Gene Induction by Hypoxia and Nitric Oxide* , 2001, The Journal of Biological Chemistry.

[72]  L. del Peso,et al.  Analysis of HIF-prolyl hydroxylases binding to substrates. , 2006, Biochemical and biophysical research communications.

[73]  D. Davis,et al.  Characterization of the Activation of Protein Tyrosine Phosphatase, Receptor-Type, Z Polypeptide 1 (PTPRZ1) by Hypoxia Inducible Factor-2 Alpha , 2010, PloS one.

[74]  T. Kietzmann,et al.  Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1α and Mediates Its Destabilization in a VHL-Independent Manner , 2007, Molecular and Cellular Biology.

[75]  G. Semenza,et al.  General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[76]  W. Risau,et al.  HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels , 1997, Mechanisms of Development.

[77]  G. Semenza,et al.  FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. , 2001 .

[78]  S. Fox,et al.  CITED4 Inhibits Hypoxia-Activated Transcription in Cancer Cells, and Its Cytoplasmic Location in Breast Cancer Is Associated with Elevated Expression of Tumor Cell Hypoxia-Inducible Factor 1α , 2004, Cancer Research.

[79]  A. Politou,et al.  Casein kinase 1 regulates human hypoxia-inducible factor HIF-1 , 2010, Journal of Cell Science.

[80]  C. Dalgard,et al.  Reversible Inactivation of HIF-1 Prolyl Hydroxylases Allows Cell Metabolism to Control Basal HIF-1* , 2005, Journal of Biological Chemistry.

[81]  Moon-Kyoung Bae,et al.  Regulation and Destabilization of HIF-1α by ARD1-Mediated Acetylation , 2002, Cell.

[82]  M. Horrocks,et al.  Hypoxia in Abdominal Aortic Aneurysm Supports a Role for HIF-1α and Ets-1 as Drivers of Matrix Metalloproteinase Upregulation in Human Aortic Smooth Muscle Cells , 2010, Journal of Vascular Research.

[83]  U. Lendahl,et al.  Notch signaling mediates hypoxia-induced tumor cell migration and invasion , 2008, Proceedings of the National Academy of Sciences.

[84]  K. Kivirikko,et al.  Roles of the human hypoxia-inducible factor (HIF)-3α variants in the hypoxia response , 2011, Cellular and Molecular Life Sciences.

[85]  R. Chen,et al.  Regulation of Hypoxia-Inducible Factor 2α Signaling by the Stress-Responsive Deacetylase Sirtuin 1 , 2009, Science.

[86]  D. Mottet,et al.  ERK activation upon hypoxia: involvement in HIF‐1 activation , 2000, FEBS letters.

[87]  Michael Q. Zhang,et al.  An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia , 2009, Nucleic acids research.

[88]  L. Poellinger,et al.  Redox-Regulated Recruitment of the Transcriptional Coactivators CREB-Binding Protein and SRC-1 to Hypoxia-Inducible Factor 1α , 2000, Molecular and Cellular Biology.

[89]  G. Semenza,et al.  The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation. , 1998, Genomics.

[90]  P. Ratcliffe,et al.  Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms , 2007, British Journal of Cancer.

[91]  D. Bangsberg,et al.  Erratum: Routine HIV testing in Botswana: A population-based study on attitudes, practices, and human rights concerns (PLoS Medicine 3,7, DOI: 10.1371/journal.pmed.0030261) , 2006 .

[92]  M. Pawlus,et al.  STAT3 and HIF1α cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells , 2014, Oncogene.

[93]  W. Dai,et al.  Plk3 Functions as an Essential Component of the Hypoxia Regulatory Pathway by Direct Phosphorylation of HIF-1α* , 2010, The Journal of Biological Chemistry.

[94]  L. Poellinger,et al.  Mechanism of regulation of the hypoxia‐inducible factor‐1α by the von Hippel‐Lindau tumor suppressor protein , 2000, The EMBO journal.

[95]  G. Semenza,et al.  Purification and Characterization of Hypoxia-inducible Factor 1 (*) , 1995, The Journal of Biological Chemistry.

[96]  Cheng-Jun Hu,et al.  Enhanceosomes as integrators of hypoxia inducible factor (HIF) and other transcription factors in the hypoxic transcriptional response. , 2013, Cellular signalling.

[97]  G. Semenza,et al.  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 , 1992, Molecular and cellular biology.

[98]  K. Kivirikko,et al.  An Endoplasmic Reticulum Transmembrane Prolyl 4-Hydroxylase Is Induced by Hypoxia and Acts on Hypoxia-inducible Factor α* , 2007, Journal of Biological Chemistry.

[99]  J. Gustafsson,et al.  Isolation and characterization of AINT: a novel ARNT interacting protein expressed during murine embryonic development , 2000, Mechanisms of Development.

[100]  J. Stamler,et al.  S-nitrosylation in health and disease. , 2003, Trends in molecular medicine.

[101]  D. Livingston,et al.  Activation of Hypoxia-inducible Transcription Factor Depends Primarily upon Redox-sensitive Stabilization of Its α Subunit* , 1996, The Journal of Biological Chemistry.

[102]  G. Panayotou,et al.  Identification of MAPK Phosphorylation Sites and Their Role in the Localization and Activity of Hypoxia-inducible Factor-1α* , 2006, Journal of Biological Chemistry.

[103]  Diego Villar,et al.  Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction , 2010, Nucleic acids research.

[104]  C. Brinckerhoff,et al.  Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2α in von Hippel–Lindau renal cell carcinoma , 2005, Oncogene.

[105]  J. Pouysségur,et al.  HIF prolyl‐hydroxylase 2 is the key oxygen sensor setting low steady‐state levels of HIF‐1α in normoxia , 2003, The EMBO journal.

[106]  Yuichi Makino,et al.  Inhibitory PAS Domain Protein (IPAS) Is a Hypoxia-inducible Splicing Variant of the Hypoxia-inducible Factor-3α Locus* , 2002, The Journal of Biological Chemistry.

[107]  O. Hankinson,et al.  Roles of Brahma and Brahma/SWI2-Related Gene 1 in Hypoxic Induction of the Erythropoietin Gene* , 2004, Journal of Biological Chemistry.

[108]  G. Semenza,et al.  Hypoxia-Inducible Factors in Physiology and Medicine , 2012, Cell.

[109]  W. Wong,et al.  Hypoxia-inducible factors and the response to hypoxic stress. , 2010, Molecular cell.

[110]  S. Bhattacharya,et al.  Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. , 1999, Genes & development.

[111]  M. Makuuchi,et al.  Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. , 2000, Blood.

[112]  G. Semenza,et al.  Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[113]  G. Camenisch,et al.  Integration of Oxygen Signaling at the Consensus HRE , 2005, Science's STKE.

[114]  Henry W. Long,et al.  HIF1A Employs CDK8-Mediator to Stimulate RNAPII Elongation in Response to Hypoxia , 2013, Cell.

[115]  Matthew K. Knabel,et al.  Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1 , 2011, Cell.

[116]  R. Evjenth,et al.  Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha. , 2005, FEBS letters.

[117]  G. Semenza,et al.  Transactivation and Inhibitory Domains of Hypoxia-inducible Factor 1α , 1997, The Journal of Biological Chemistry.

[118]  K. Aldape,et al.  Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation , 2011, Nature.

[119]  G. Semenza,et al.  Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation , 2011, Proceedings of the National Academy of Sciences.

[120]  G. Wilson,et al.  Ref‐1/Ape is critical for formation of the hypoxia‐inducible transcriptional complex on the hypoxic response element of the rat pulmonary artery endothelial cell VEGF gene , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[121]  Leping Li,et al.  NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. , 2008, Genes & development.

[122]  Y. Miyagi,et al.  HIF2α-Sp1 interaction mediates a deacetylation-dependent FVII-gene activation under hypoxic conditions in ovarian cancer cells , 2012, Nucleic acids research.

[123]  Ru Wei,et al.  The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth , 2008, Nature.

[124]  R. Fernandes,et al.  The Chaperone-Dependent Ubiquitin Ligase CHIP Targets HIF-1α for Degradation in the Presence of Methylglyoxal , 2010, PloS one.

[125]  Robert T. Taylor,et al.  Recruitment of Thyroid Hormone Receptor/Retinoblastoma-interacting Protein 230 by the Aryl Hydrocarbon Receptor Nuclear Translocator Is Required for the Transcriptional Response to Both Dioxin and Hypoxia* , 2004, Journal of Biological Chemistry.

[126]  L. Poellinger,et al.  Role of CBP in regulating HIF-1-mediated activation of transcription , 2005, Journal of Cell Science.

[127]  G. Powis,et al.  Passing the baton: the HIF switch. , 2012, Trends in biochemical sciences.

[128]  Jiannis Ragoussis,et al.  Genome-wide Association of Hypoxia-inducible Factor (HIF)-1α and HIF-2α DNA Binding with Expression Profiling of Hypoxia-inducible Transcripts , 2009, The Journal of Biological Chemistry.

[129]  R. Nagai,et al.  Endothelial PAS Domain Protein 1 Gene Promotes Angiogenesis Through the Transactivation of Both Vascular Endothelial Growth Factor and Its Receptor, Flt-1 , 2004, Circulation research.

[130]  Jessica Lo,et al.  HIF‐1α is required for solid tumor formation and embryonic vascularization , 1998 .

[131]  Hugo J. Bellen,et al.  Notch Signaling , 2014, Methods in Molecular Biology.

[132]  Y. Fujii‐Kuriyama,et al.  Abnormal Heart Development and Lung Remodeling in Mice Lacking the Hypoxia-Inducible Factor-Related Basic Helix-Loop-Helix PAS Protein NEPAS , 2007, Molecular and Cellular Biology.

[133]  Huasheng Lu,et al.  Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis* , 2002, The Journal of Biological Chemistry.

[134]  U. Lendahl,et al.  Generating specificity and diversity in the transcriptional response to hypoxia , 2009, Nature Reviews Genetics.

[135]  Till Acker,et al.  Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice , 2002, Nature Medicine.

[136]  M. Ohh,et al.  The updated biology of hypoxia‐inducible factor , 2012, The EMBO journal.

[137]  L. Huang,et al.  CITED2 controls the hypoxic signaling by snatching p300 from the two distinct activation domains of HIF-1α. , 2011, Biochimica et biophysica acta.

[138]  E. Berra,et al.  Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade , 2013, Biological chemistry.

[139]  A. Dopazo,et al.  Cooperativity of Stress-Responsive Transcription Factors in Core Hypoxia-Inducible Factor Binding Regions , 2012, PloS one.

[140]  L. Huang,et al.  Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway , 1998 .

[141]  Tyson V. Sharp,et al.  The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity , 2012, Nature Cell Biology.

[142]  D. Hwang,et al.  Hypoxia-induced methylation of a pontin chromatin remodeling factor , 2011, Proceedings of the National Academy of Sciences.

[143]  Kyu-Won Kim,et al.  Sumoylation increases HIF-1α stability and its transcriptional activity , 2004 .

[144]  Chris T. Harvey,et al.  HDAC4 Protein Regulates HIF1α Protein Lysine Acetylation and Cancer Cell Response to Hypoxia* , 2011, The Journal of Biological Chemistry.

[145]  E. Yang,et al.  Modulation of p300 binding by posttranslational modifications of the C‐terminal activation domain of hypoxia‐inducible factor‐1α , 2007, FEBS letters.

[146]  G. Semenza,et al.  HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression , 2001, Molecular and Cellular Biology.

[147]  Gerhard Wagner,et al.  Structural basis for negative regulation of hypoxia-inducible factor-1α by CITED2 , 2003, Nature Structural Biology.

[148]  M. A. Morris,et al.  The HIF family member EPAS 1 / HIF-2 is required for normal hematopoiesis in mice , 2003 .

[149]  G. Semenza,et al.  Hsp70 and CHIP Selectively Mediate Ubiquitination and Degradation of Hypoxia-inducible Factor (HIF)-1α but Not HIF-2α* , 2009, The Journal of Biological Chemistry.

[150]  J. Pouysségur,et al.  SUMOylation of hypoxia-inducible factor-1α reduces its transcriptional activity , 2007 .

[151]  S. McKnight,et al.  Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. , 1997, Genes & development.

[152]  O. Hankinson,et al.  Roles of Coactivators in Hypoxic Induction of the Erythropoietin Gene , 2010, PloS one.

[153]  A. Zhitkovich,et al.  Depletion of Intracellular Ascorbate by the Carcinogenic Metals Nickel and Cobalt Results in the Induction of Hypoxic Stress* , 2004, Journal of Biological Chemistry.

[154]  Christopher B. Burge,et al.  c-Myc Regulates Transcriptional Pause Release , 2010, Cell.

[155]  Huaxi Xu,et al.  Transcriptional regulation of APH‐1A and increased γ‐secretase cleavage of APP and Notch by HIF‐1 and hypoxia , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[156]  R. Roeder,et al.  Complex Regulation of the Transactivation Function of Hypoxia-inducible Factor-1α by Direct Interaction with Two Distinct Domains of the CREB-binding Protein/p300* , 2009, The Journal of Biological Chemistry.

[157]  Kou-Juey Wu,et al.  Hypoxia-regulated target genes implicated in tumor metastasis , 2012, Journal of Biomedical Science.

[158]  R. Chen,et al.  The Acetylase/Deacetylase Couple CREB-binding Protein/Sirtuin 1 Controls Hypoxia-inducible Factor 2 Signaling* , 2012, The Journal of Biological Chemistry.

[159]  A. Bertolin,et al.  Drosophila Genome-Wide RNAi Screen Identifies Multiple Regulators of HIF–Dependent Transcription in Hypoxia , 2010, PLoS genetics.

[160]  B. Ebert,et al.  Regulation of Transcription by Hypoxia Requires a Multiprotein Complex That Includes Hypoxia-Inducible Factor 1, an Adjacent Transcription Factor, and p300/CREB Binding Protein , 1998, Molecular and Cellular Biology.

[161]  H. Dyson,et al.  Structural basis for Hif-1α/CBP recognition in the cellular hypoxic response , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[162]  K. Gardner,et al.  Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B , 2011, Proceedings of the National Academy of Sciences.

[163]  B. Brüne,et al.  High glucose concentrations attenuate hypoxia-inducible factor-1alpha expression and signaling in non-tumor cells. , 2010, Experimental cell research.

[164]  N. Oldham,et al.  Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF‐1α fragments in vitro , 2006, FEBS letters.

[165]  G. Semenza,et al.  Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. , 1993, The Journal of biological chemistry.

[166]  S. Rocha,et al.  SWI/SNF Regulates the Cellular Response to Hypoxia* , 2009, Journal of Biological Chemistry.

[167]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[168]  P. Carmeliet,et al.  Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice , 2002, Nature Medicine.

[169]  D. Mottet,et al.  Regulation of Hypoxia-inducible Factor-1α Protein Level during Hypoxic Conditions by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3β Pathway in HepG2 Cells* , 2003, Journal of Biological Chemistry.

[170]  Brian E. McIntosh,et al.  Mammalian Per-Arnt-Sim proteins in environmental adaptation. , 2010, Annual review of physiology.

[171]  Brian Keith,et al.  Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation , 2003, Molecular and Cellular Biology.

[172]  Oliver Hankinson,et al.  Role of Mediator in Transcriptional Activation by the Aryl Hydrocarbon Receptor* , 2004, Journal of Biological Chemistry.

[173]  M. Wood,et al.  Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. , 2006, Cancer research.

[174]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[175]  H. Yee,et al.  Regulation of hypoxia-inducible genes by ETS1 transcription factor. , 2008, Carcinogenesis.

[176]  M. Jewett,et al.  Human HIF‐3α4 is a dominant‐negative regulator of HIF‐1 and is down‐regulated in renal cell carcinoma , 2005 .

[177]  G. Semenza Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. , 2012, Trends in pharmacological sciences.

[178]  P. Ratcliffe,et al.  Pan-genomic binding of hypoxia-inducible transcription factors , 2013, Biological chemistry.