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PMID: 22169972 Published · epublish English Journal Article Review

HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression.

Nature reviews. Cancer ·Vol. 12 ·No. 1 ·2011-12-15 ·Pages 9-22

Keith B, Johnson RS, Simon MC

Abstract

Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.

MeSH Terms
Acetylation Animals Basic Helix-Loop-Helix Transcription Factors/physiology Cell Hypoxia Cell Proliferation Disease Progression Gene Expression Regulation Genes, myc Genes, p53 Humans Hypoxia-Inducible Factor 1, alpha Subunit/physiology Mechanistic Target of Rapamycin Complex 1 Multiprotein Complexes Neoplasms/pathology Protein Processing, Post-Translational Proteins/physiology TOR Serine-Threonine Kinases
Chemicals
Basic Helix-Loop-Helix Transcription Factors Hypoxia-Inducible Factor 1, alpha Subunit Multiprotein Complexes Proteins endothelial PAS domain-containing protein 1 Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Keith Brian
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Johnson Randall S
Simon M Celeste
References (192)
192 references, click to expand
  1. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs.
    FASEB J. 2003 Feb;17(2):271-3 PMID: 12490539
  2. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1.
    EMBO J. 2006 Mar 22;25(6):1231-41 PMID: 16511565
  3. Targeting HIF-1 for cancer therapy.
    Nat Rev Cancer. 2003 Oct;3(10):721-32 PMID: 13130303
  4. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway.
    J Biol Chem. 1997 Mar 28;272(13):8581-93 PMID: 9079689
  5. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb.
    J Biol Chem. 2007 Dec 7;282(49):35803-13 PMID: 17928295
  6. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.
    Genes Dev. 2000 Jan 1;14(1):34-44 PMID: 10640274
  7. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation.
    Cell Metab. 2005 Jun;1(6):393-9 PMID: 16054088
  8. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels.
    Mech Dev. 1997 Apr;63(1):51-60 PMID: 9178256
  9. O2 regulates stem cells through Wnt/β-catenin signalling.
    Nat Cell Biol. 2010 Oct;12(10):1007-13 PMID: 20852629
  10. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth.
    Cancer Res. 2000 Aug 1;60(15):4010-5 PMID: 10945599
  11. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.
    Genes Dev. 2006 Mar 1;20(5):557-70 PMID: 16510872
  12. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.
    Cancer Cell. 2002 Apr;1(3):237-46 PMID: 12086860
  13. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.
    Genes Dev. 2004 Dec 1;18(23):2893-904 PMID: 15545625
  14. HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses.
    Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14391-6 PMID: 19706526
  15. siRNA-mediated knockdown of aryl hydrocarbon receptor nuclear translocator 2 affects hypoxia-inducible factor-1 regulatory signaling and metabolism in human breast cancer cells.
    FEBS Lett. 2011 Oct 20;585(20):3310-5 PMID: 21945317
  16. Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma.
    Clin Cancer Res. 2007 Dec 15;13(24):7388-93 PMID: 18094421
  17. Hypoxia-inducible factor-1alpha expression and angiogenesis in gastrointestinal stromal tumor of the stomach.
    Oncol Rep. 2003 Jul-Aug;10(4):797-802 PMID: 12792726
  18. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation.
    Cell. 2002 Nov 27;111(5):709-20 PMID: 12464182
  19. Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.
    J Biol Chem. 2003 Apr 18;278(16):13595-8 PMID: 12606552
  20. HIF-2alpha deletion promotes Kras-driven lung tumor development.
    Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14182-7 PMID: 20660313
  21. AKT-ing via microRNA.
    Cell Cycle. 2010 Aug 15;9(16):3213-7 PMID: 20814244
  22. HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin.
    EMBO J. 2003 Mar 3;22(5):1134-46 PMID: 12606578
  23. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth.
    PLoS Biol. 2003 Dec;1(3):E83 PMID: 14691554
  24. The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction.
    Biochem J. 2009 Oct 23;424(1):143-51 PMID: 19694616
  25. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.
    Genes Dev. 2001 Oct 15;15(20):2675-86 PMID: 11641274
  26. Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer.
    Anticancer Res. 2003 Nov-Dec;23(6C):4721-7 PMID: 14981919
  27. Kidney cancer: now available in a new flavor.
    Cancer Cell. 2008 Dec 9;14(6):423-4 PMID: 19061830
  28. Common corruption of the mTOR signaling network in human tumors.
    Oncogene. 2008 Dec;27 Suppl 2:S43-51 PMID: 19956179
  29. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis.
    Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4260-5 PMID: 19255431
  30. RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia.
    Cell. 2007 Oct 19;131(2):309-23 PMID: 17956732
  31. The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling.
    Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8386-91 PMID: 10880563
  32. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4 PMID: 7539918
  33. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex.
    J Biol Chem. 2003 Mar 28;278(13):11032-40 PMID: 12538644
  34. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation.
    J Clin Invest. 2010 Aug;120(8):2699-714 PMID: 20644254
  35. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress.
    Mol Cell. 2010 Oct 22;40(2):310-22 PMID: 20965424
  36. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.
    Cancer Cell. 2009 Jun 2;15(6):501-13 PMID: 19477429
  37. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma.
    Cancer Cell. 2008 Dec 9;14(6):435-46 PMID: 19061835
  38. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization.
    Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17910-5 PMID: 19805192
  39. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice.
    Nat Genet. 2003 Dec;35(4):331-40 PMID: 14608355
  40. Sumoylation increases HIF-1alpha stability and its transcriptional activity.
    Biochem Biophys Res Commun. 2004 Nov 5;324(1):394-400 PMID: 15465032
  41. Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer.
    Breast Cancer Res Treat. 2008 Aug;110(3):465-75 PMID: 17805961
  42. SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia.
    Cell. 2007 Nov 2;131(3):584-95 PMID: 17981124
  43. Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.
    Cancer Res. 2008 Nov 15;68(22):9212-20 PMID: 19010893
  44. HIF-1 alpha is required for solid tumor formation and embryonic vascularization.
    EMBO J. 1998 Jun 1;17(11):3005-15 PMID: 9606183
  45. 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.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4273-8 PMID: 9113979
  46. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation.
    Cell Metab. 2005 Jun;1(6):409-14 PMID: 16054090
  47. Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.
    Clin Cancer Res. 2004 Dec 15;10(24):8554-60 PMID: 15623639
  48. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha.
    Mol Cell Biol. 2006 Mar;26(6):2019-28 PMID: 16507982
  49. Identification of FIP200 interaction with the TSC1-TSC2 complex and its role in regulation of cell size control.
    J Cell Biol. 2005 Aug 1;170(3):379-89 PMID: 16043512
  50. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
    Mol Cell. 2008 May 23;30(4):393-402 PMID: 18498744
  51. The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion.
    Cancer Res. 2011 Jun 1;71(11):4015-27 PMID: 21512133
  52. The role of HIF prolyl hydroxylases in tumour growth.
    J Cell Mol Med. 2010 Apr;14(4):758-70 PMID: 20178464
  53. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice.
    Oncogene. 2008 Sep 11;27(40):5354-8 PMID: 18490920
  54. Binding of natively unfolded HIF-1alpha ODD domain to p53.
    Mol Cell. 2005 Jan 7;17(1):11-21 PMID: 15629713
  55. Correlations of hypoxia-inducible factor-1α/hypoxia-inducible factor-2α expression with angiogenesis factors expression and prognosis in non-small cell lung cancer.
    Chin Med J (Engl). 2011 Jan;124(1):11-8 PMID: 21362301
  56. HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia.
    Exp Cell Res. 2005 Feb 15;303(2):447-56 PMID: 15652356
  57. Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells.
    Cancer Res. 2002 May 1;62(9):2478-82 PMID: 11980636
  58. The interplay between MYC and HIF in cancer.
    Nat Rev Cancer. 2008 Jan;8(1):51-6 PMID: 18046334
  59. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus.
    J Biol Chem. 2002 Sep 6;277(36):32405-8 PMID: 12119283
  60. Relationship of hypoxia-inducible factor 1alpha and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer.
    World J Surg Oncol. 2006 Dec 13;4:94 PMID: 17166265
  61. Recent progress in the biology and physiology of sirtuins.
    Nature. 2009 Jul 30;460(7255):587-91 PMID: 19641587
  62. Acute postnatal ablation of Hif-2alpha results in anemia.
    Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2301-6 PMID: 17284606
  63. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity.
    Cancer Cell. 2005 Aug;8(2):99-110 PMID: 16098463
  64. RNF4 and VHL regulate the proteasomal degradation of SUMO-conjugated Hypoxia-Inducible Factor-2alpha.
    Nucleic Acids Res. 2010 Apr;38(6):1922-31 PMID: 20026589
  65. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production.
    Oncogene. 2011 Jun 30;30(26):2986-96 PMID: 21358671
  66. Neuromuscular abundance of RB1CC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation.
    Int J Mol Med. 2006 Sep;18(3):425-32 PMID: 16865226
  67. The role of oxygen availability in embryonic development and stem cell function.
    Nat Rev Mol Cell Biol. 2008 Apr;9(4):285-96 PMID: 18285802
  68. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.
    Nature. 2008 Jun 5;453(7196):807-11 PMID: 18432192
  69. Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis.
    Cancer Biol Ther. 2005 Nov;4(11):1285-94 PMID: 16319523
  70. Hypoxia-associated markers in gastric carcinogenesis and HIF-2alpha in gastric and gastro-oesophageal cancer prognosis.
    Br J Cancer. 2008 Mar 11;98(5):965-73 PMID: 18283323
  71. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.
    Blood. 2009 Jul 23;114(4):844-59 PMID: 19454749
  72. Hypoxia-inducible factor α subunit stabilization by NEDD8 conjugation is reactive oxygen species-dependent.
    J Biol Chem. 2011 Mar 4;286(9):6963-70 PMID: 21193393
  73. Prognostic significance of Hypoxia-Inducible Factor 1 alpha(HIF-1 alpha) expression in serous ovarian cancer: an immunohistochemical study.
    BMC Cancer. 2008 Nov 16;8:335 PMID: 19014607
  74. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor.
    J Biol Chem. 2004 Sep 10;279(37):38458-65 PMID: 15247232
  75. Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression.
    Cell Cycle. 2007 Nov 15;6(22):2810-6 PMID: 17998805
  76. Hypoxia-inducible factors 1alpha and 2alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin.
    Melanoma Res. 2003 Oct;13(5):493-501 PMID: 14512791
  77. Hypoxia-induced energy stress regulates mRNA translation and cell growth.
    Mol Cell. 2006 Feb 17;21(4):521-31 PMID: 16483933
  78. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression.
    Cancer Res. 2010 Oct 1;70(19):7465-75 PMID: 20841473
  79. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.
    Blood. 2010 Oct 21;116(16):3039-48 PMID: 20628150
  80. The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression.
    EMBO J. 2006 Oct 18;25(20):4784-94 PMID: 17024177
  81. Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis.
    Blood. 2009 Jul 9;114(2):469-77 PMID: 19439736
  82. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB.
    Biochem J. 2006 Jun 15;396(3):517-27 PMID: 16533170
  83. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.
    Cancer Cell. 2011 Mar 8;19(3):416-28 PMID: 21397863
  84. Blinded by the Light: The Growing Complexity of p53.
    Cell. 2009 May 1;137(3):413-31 PMID: 19410540
  85. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.
    Genes Dev. 1998 Jan 15;12(2):149-62 PMID: 9436976
  86. Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival.
    Br J Cancer. 2001 Sep 14;85(6):881-90 PMID: 11556841
  87. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.
    J Clin Invest. 2007 Apr;117(4):1068-77 PMID: 17404621
  88. FIH-dependent asparaginyl hydroxylation of ankyrin repeat domain-containing proteins.
    Ann N Y Acad Sci. 2009 Oct;1177:9-18 PMID: 19845602
  89. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer.
    Nat Rev Cancer. 2008 Nov;8(11):865-73 PMID: 18923434
  90. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3.
    Nat Genet. 2011 Jan;43(1):60-5 PMID: 21131975
  91. The SirT3 divining rod points to oxidative stress.
    Mol Cell. 2011 Jun 10;42(5):561-8 PMID: 21658599
  92. Genetic evidence for a tumor suppressor role of HIF-2alpha.
    Cancer Cell. 2005 Aug;8(2):131-41 PMID: 16098466
  93. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.
    EMBO J. 2004 May 5;23(9):1949-56 PMID: 15071503
  94. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.
    Nat Med. 2004 Jun;10(6):594-601 PMID: 15156201
  95. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.
    Genes Dev. 2002 Jun 15;16(12):1466-71 PMID: 12080085
  96. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.
    Cell Metab. 2005 Jun;1(6):401-8 PMID: 16054089
  97. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.
    Mol Cell. 2005 Mar 18;17(6):793-803 PMID: 15780936
  98. Target gene selectivity of hypoxia-inducible factor-alpha in renal cancer cells is conveyed by post-DNA-binding mechanisms.
    Br J Cancer. 2007 Apr 23;96(8):1284-92 PMID: 17387348
  99. Suppression of hypoxia-inducible factor 2alpha restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells.
    Cancer Res. 2009 Dec 1;69(23):9056-64 PMID: 19920202
  100. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha.
    Mol Biol Cell. 2007 Nov;18(11):4528-42 PMID: 17804822
  101. PHD2 in tumour angiogenesis.
    Br J Cancer. 2010 Jun 29;103(1):1-5 PMID: 20461086
  102. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development.
    Genes Dev. 1998 Nov 1;12(21):3320-4 PMID: 9808618
  103. Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1alpha and is not induced by hypoxia or HIF.
    J Biol Chem. 2005 Sep 2;280(35):31132-40 PMID: 15994306
  104. Hypoxia requires notch signaling to maintain the undifferentiated cell state.
    Dev Cell. 2005 Nov;9(5):617-28 PMID: 16256737
  105. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts.
    J Biol Chem. 2009 Jun 19;284(25):16767-16775 PMID: 19386601
  106. HIF-1: upstream and downstream of cancer metabolism.
    Curr Opin Genet Dev. 2010 Feb;20(1):51-6 PMID: 19942427
  107. Hypoxia-inducible factors and the response to hypoxic stress.
    Mol Cell. 2010 Oct 22;40(2):294-309 PMID: 20965423
  108. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis.
    Genes Dev. 2010 Mar 1;24(5):491-501 PMID: 20194441
  109. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.
    Nat Med. 2002 Jul;8(7):702-10 PMID: 12053176
  110. ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus.
    Mech Dev. 2000 Feb;90(2):253-61 PMID: 10640708
  111. The HIF pathway and erythrocytosis.
    Annu Rev Pathol. 2011;6:165-92 PMID: 20939709
  112. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia.
    Nat Cell Biol. 2007 Feb;9(2):210-7 PMID: 17220880
  113. Hypoxia-inducible factor 1alpha/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis.
    Neuropathol Appl Neurobiol. 2004 Jun;30(3):267-78 PMID: 15175080
  114. The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
    Cell Metab. 2010 May 5;11(5):364-78 PMID: 20399150
  115. mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α.
    Mol Cell. 2010 Nov 24;40(4):509-20 PMID: 21095582
  116. Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth.
    Mol Cell Biol. 2010 Jan;30(1):344-53 PMID: 19858293
  117. Prognostic significance of co-overexpression of the EGFR/IGFBP-2/HIF-2A genes in astrocytomas.
    J Neurooncol. 2007 Jul;83(3):233-9 PMID: 17285230
  118. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation.
    Mol Cell Biol. 2003 Dec;23(24):9361-74 PMID: 14645546
  119. HIF-1alpha and HIF-2alpha are differentially regulated in vivo in neuroblastoma: high HIF-1alpha correlates negatively to advanced clinical stage and tumor vascularization.
    Clin Cancer Res. 2009 Dec 1;15(23):7130-6 PMID: 19903792
  120. Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1.
    J Biol Chem. 2008 Jul 4;283(27):18926-36 PMID: 18434321
  121. Hypoxia-inducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas.
    Br J Cancer. 2007 Jan 15;96(1):95-103 PMID: 17179985
  122. Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2.
    J Biol Chem. 2008 Dec 12;283(50):34495-9 PMID: 18945681
  123. Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha.
    J Biol Chem. 2010 Feb 5;285(6):3651-3663 PMID: 19940151
  124. Regulation of HIF-1alpha stability through S-nitrosylation.
    Mol Cell. 2007 Apr 13;26(1):63-74 PMID: 17434127
  125. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules.
    Cancer Cell. 2004 May;5(5):429-41 PMID: 15144951
  126. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway.
    J Biol Chem. 2002 Aug 16;277(33):29936-44 PMID: 12052835
  127. The complexity of p53 stabilization and activation.
    Cell Death Differ. 2006 Jun;13(6):941-50 PMID: 16601750
  128. Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer.
    Eur Urol. 2004 Aug;46(2):200-8 PMID: 15245814
  129. Roles of the human hypoxia-inducible factor (HIF)-3α variants in the hypoxia response.
    Cell Mol Life Sci. 2011 Dec;68(23):3885-901 PMID: 21479871
  130. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer.
    Cancer Res. 2000 Sep 1;60(17):4693-6 PMID: 10987269
  131. Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner.
    J Biol Chem. 2011 Apr 22;286(16):13869-78 PMID: 21345792
  132. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family.
    J Biol Chem. 2002 Jul 19;277(29):26351-5 PMID: 12042299
  133. Making a tumour's bed: glioblastoma stem cells and the vascular niche.
    Nat Rev Cancer. 2007 Oct;7(10):733-6 PMID: 17882276
  134. Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells.
    J Biol Chem. 2003 Nov 7;278(45):44966-74 PMID: 12944410
  135. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq.
    Blood. 2011 Jun 9;117(23):e207-17 PMID: 21447827
  136. Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel-Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma.
    Hum Pathol. 2007 Sep;38(9):1310-20 PMID: 17555795
  137. Casein kinase 1 regulates human hypoxia-inducible factor HIF-1.
    J Cell Sci. 2010 Sep 1;123(Pt 17):2976-86 PMID: 20699359
  138. Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer.
    J Clin Invest. 2009 May;119(5):1093-108 PMID: 19363294
  139. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha.
    Cancer Res. 2006 Sep 1;66(17):8814-21 PMID: 16951198
  140. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.
    Mol Cell Biol. 2005 Jul;25(13):5675-86 PMID: 15964822
  141. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer.
    Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1192-202 PMID: 12128120
  142. The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer.
    Cancer. 2006 Aug 15;107(4):757-66 PMID: 16826581
  143. p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment.
    Oncogene. 2004 Jun 24;23(29):4975-83 PMID: 15107830
  144. Prognostic significance of HIF-2alpha expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy.
    J Med Invest. 2008 Feb;55(1-2):78-86 PMID: 18319549
  145. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.
    Cancer Cell. 2007 May;11(5):407-20 PMID: 17482131
  146. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation.
    EMBO J. 2009 Sep 16;28(18):2748-62 PMID: 19680224
  147. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1.
    Science. 2009 Jun 5;324(5932):1289-93 PMID: 19498162
  148. The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma.
    Clin Cancer Res. 2005 Feb 1;11(3):1129-35 PMID: 15709180
  149. The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma.
    Cancer Cell. 2002 Apr;1(3):247-55 PMID: 12086861
  150. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice.
    J Clin Invest. 2009 May;119(5):1159-66 PMID: 19352007
  151. Preferential binding of HIF-1 to transcriptionally active loci determines cell-type specific response to hypoxia.
    Genome Biol. 2009;10(10):R113 PMID: 19828020
  152. HIN-1, an inhibitor of cell growth, invasion, and AKT activation.
    Cancer Res. 2005 Nov 1;65(21):9659-69 PMID: 16266985
  153. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation.
    Mol Cell Biol. 2008 Dec;28(23):7081-95 PMID: 18838541
  154. Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing.
    Mol Cell. 2008 Dec 26;32(6):838-48 PMID: 19111663
  155. Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells.
    Mol Biol Cell. 2007 Dec;18(12):4691-7 PMID: 17898080
  156. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1.
    Mol Cell Biol. 2007 Nov;27(21):7381-93 PMID: 17785433
  157. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer.
    Nat Med. 2006 Jan;12(1):122-7 PMID: 16341243
  158. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency.
    Nat Struct Mol Biol. 2007 May;14(5):420-6 PMID: 17417656
  159. Cell-specific regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha stabilization and transactivation in a graded oxygen environment.
    J Biol Chem. 2006 Aug 11;281(32):22575-85 PMID: 16760477
  160. The role of hypoxia-inducible factors in tumorigenesis.
    Cell Death Differ. 2008 Apr;15(4):678-85 PMID: 18259193
  161. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway.
    Cancer Res. 2002 Aug 1;62(15):4316-24 PMID: 12154035
  162. Heterozygosity for hypoxia inducible factor 1alpha decreases the incidence of thymic lymphomas in a p53 mutant mouse model.
    Cancer Res. 2009 Apr 1;69(7):3213-20 PMID: 19293180
  163. HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice.
    J Clin Invest. 2009 Aug;119(8):2160-70 PMID: 19662677
  164. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.
    Oncogene. 2010 Feb 4;29(5):625-34 PMID: 19946328
  165. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.
    Nature. 1998 Jul 30;394(6692):485-90 PMID: 9697772
  166. Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha.
    J Biol Chem. 2004 Apr 9;279(15):14871-8 PMID: 14744852
  167. Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis.
    Cancer Cell. 2004 Nov;6(5):485-95 PMID: 15542432
  168. Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney.
    Cancer Res. 2009 Jun 1;69(11):4674-81 PMID: 19470766
  169. HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells.
    Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16805-10 PMID: 19805377
  170. Combinatorial regulation of neuroblastoma tumor progression by N-Myc and hypoxia inducible factor HIF-1alpha.
    Cancer Res. 2010 Dec 15;70(24):10351-61 PMID: 20961996
  171. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype.
    Cancer Cell. 2006 Nov;10(5):413-23 PMID: 17097563
  172. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha.
    Mol Cell. 2010 Jun 25;38(6):864-78 PMID: 20620956
  173. Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma.
    World J Gastroenterol. 2007 Jun 21;13(23):3176-82 PMID: 17589895
  174. Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer.
    Lung Cancer. 2005 Sep;49(3):325-35 PMID: 15935515
  175. cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt).
    Mol Cell Biol. 1996 Apr;16(4):1706-13 PMID: 8657146
  176. Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis.
    Int J Oncol. 2007 Jun;30(6):1359-67 PMID: 17487356
  177. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.
    Cell. 2010 Jan 22;140(2):280-93 PMID: 20141841
  178. The impact of O2 availability on human cancer.
    Nat Rev Cancer. 2008 Dec;8(12):967-75 PMID: 18987634
  179. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.
    Genes Dev. 1997 Jan 1;11(1):72-82 PMID: 9000051
  180. Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt.
    Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6692-7 PMID: 11381139
  181. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
    Nature. 2010 Jan 21;463(7279):360-3 PMID: 20054297
  182. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1.
    J Biol Chem. 1999 Nov 12;274(46):32631-7 PMID: 10551817
  183. Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma.
    Anticancer Res. 2009 Nov;29(11):4337-43 PMID: 20032376
  184. SWI/SNF regulates the cellular response to hypoxia.
    J Biol Chem. 2009 Feb 13;284(7):4123-31 PMID: 19097995
  185. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling.
    Genes Dev. 2008 Jan 15;22(2):239-51 PMID: 18198340
  186. EPAS1 trans-activation during hypoxia requires p42/p44 MAPK.
    J Biol Chem. 1999 Nov 19;274(47):33709-13 PMID: 10559262
  187. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha.
    J Biol Chem. 2006 Nov 3;281(44):33095-106 PMID: 16954218
  188. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression.
    Cancer Res. 2007 Jan 15;67(2):563-72 PMID: 17234764
  189. Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha.
    Nature. 1998 Mar 26;392(6674):405-8 PMID: 9537326
  190. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity.
    Cancer Cell. 2007 Apr;11(4):335-47 PMID: 17418410
  191. Hypoxia signalling in cancer and approaches to enforce tumour regression.
    Nature. 2006 May 25;441(7092):437-43 PMID: 16724055
  192. Interdependence of hypoxic and innate immune responses.
    Nat Rev Immunol. 2009 Sep;9(9):609-17 PMID: 19704417
Article Info
Journal
Nature reviews. Cancer
Abbr.
Nat Rev Cancer
ISSN
1474-1768
DOI
10.1038/nrc3183
Published
2011-12-15
Epub
2011-00-15
Pages
9-22
Language
English
Region
England
NLM ID
101124168
PMCID
PMC3401912
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NCI NIH HHS · R01 CA158301 · United States
NHLBI NIH HHS · R01 HL066310 · United States
External Links
PubMed source DOI: 10.1038/nrc3183 PMC Full Text View journal details
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