HIF1A: Difference between revisions

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{{Infobox_gene}}
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'''Hypoxia-inducible factor 1-alpha''', also known as '''HIF-1-alpha''', is a subunit of a heterodimeric [[transcription factor]] hypoxia-inducible factor 1 ([[HIF-1]]) that is encoded by the ''HIF1A'' [[gene]].<ref name="pmid8786149">{{cite journal | vauthors = Semenza GL, Rue EA, Iyer NV, Pang MG, Kearns WG | title = Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q | journal = Genomics | volume = 34 | issue = 3 | pages = 437–9 | date = June 1996 | pmid = 8786149 | doi = 10.1006/geno.1996.0311 }}</ref><ref name="pmid9079689">{{cite journal | vauthors = Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA | title = Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway | journal = J. Biol. Chem. | volume = 272 | issue = 13 | pages = 8581–93 | date = March 1997 | pmid = 9079689 | doi = 10.1074/jbc.272.13.8581 }}</ref><ref name = "entrez"/> It is a [[basic helix-loop-helix]] [[PAS domain]] containing [[protein]], and is considered as the master [[transcriptional regulator]] of cellular and developmental response to [[hypoxia (medical)|hypoxia]].<ref name="pmid7539918">{{cite journal | vauthors = Wang GL, Jiang BH, Rue EA, Semenza GL | title = Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 12 | pages = 5510–5514 | date = Jun 1995 | pmid = 7539918 | pmc = 41725 | doi=10.1073/pnas.92.12.5510}}</ref><ref>{{cite journal | vauthors = Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL | title = Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha | journal = Genes & Development | volume = 12 | issue = 2 | pages = 149–62 | date = Jan 1998 | pmid = 9436976 | doi = 10.1101/gad.12.2.149 | pmc=316445}}</ref> The dysregulation and overexpression of ''HIF1A'' by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of [[vascularization]] and [[angiogenesis]], energy [[metabolism]], cell survival, and tumor invasion.<ref name = "entrez"/><ref name="Targeting HIF-1 for cancer therapy">{{cite journal | vauthors = Semenza GL | title = Targeting HIF-1 for cancer therapy | journal = Nature Reviews. Cancer | volume = 3 | issue = 10 | pages = 721–32 | date = Oct 2003 | pmid = 13130303 | doi = 10.1038/nrc1187 }}</ref> Two other [[alternative splicing|alternative transcripts]] encoding different [[isoforms]] have been identified.<ref name = "entrez">{{cite web | title = Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3091 }}</ref>
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'''Hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)''', also known as '''HIF1A''', is a human [[gene]].
<!-- This infobox is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = PBB_Protein_HIF1A_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1h2k.
| PDB = {{PDB2|1h2k}}, {{PDB2|1h2l}}, {{PDB2|1h2m}}, {{PDB2|1l3e}}, {{PDB2|1l8c}}, {{PDB2|1lqb}}
| Name = Hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)
| HGNCid = 4910
| Symbol = HIF1A
| AltSymbols =; HIF-1alpha; HIF1-ALPHA; MOP1; PASD8
| OMIM = 603348
  | ECnumber =
| Homologene = 1171
| MGIid = 106918
| GeneAtlas_image1 = PBB_GE_HIF1A_200989_at.png
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = 17:26, 11 September 2007 (UTC)
| Function = {{GNF_GO|id=GO:0003705 |text = RNA polymerase II transcription factor activity, enhancer binding}} {{GNF_GO|id=GO:0004871 |text = signal transducer activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0035035 |text = histone acetyltransferase binding}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}}
  | Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0009434 |text = microtubule-based flagellum}}
| Process = {{GNF_GO|id=GO:0001525 |text = angiogenesis}} {{GNF_GO|id=GO:0001666 |text = response to hypoxia}} {{GNF_GO|id=GO:0001755 |text = neural crest cell migration}} {{GNF_GO|id=GO:0001947 |text = heart looping}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}} {{GNF_GO|id=GO:0042592 |text = homeostatic process}} {{GNF_GO|id=GO:0042981 |text = regulation of apoptosis}} {{GNF_GO|id=GO:0045941 |text = positive regulation of transcription}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3091
    | Hs_Ensembl = ENSG00000100644
    | Hs_RefseqProtein = NP_001521
    | Hs_RefseqmRNA = NM_001530
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 14
    | Hs_GenLoc_start = 61231992
    | Hs_GenLoc_end = 61284729
    | Hs_Uniprot = Q16665
    | Mm_EntrezGene = 15251
    | Mm_Ensembl = ENSMUSG00000021109
    | Mm_RefseqmRNA = NM_010431
    | Mm_RefseqProtein = NP_034561
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 12
    | Mm_GenLoc_start = 74826742
    | Mm_GenLoc_end = 74866392
    | Mm_Uniprot = Q3UCW2
  }}
}}
<!-- This summary is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text = The protein encoded by HIF1 is a [[transcription factor]] found in mammalian cells growing at low oxygen concentrations. It plays an essential role in cellular and systemic responses to [[Hypoxia (medical)|hypoxia]].<ref>{{cite journal | author=Ratcliffe PJ |title=From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway. |journal=Blood Purif. |volume=20 |issue= 5 |pages= 445-50 |year= 2003 |pmid= 12207089}}</ref> This is one of the class of [[hypoxia inducible factors]].


HIF1 is a heterodimer composed of an alpha subunit and a beta subunit. The beta subunit has been identified as the aryl hydrocarbon receptor nuclear translocator (ARNT). This gene encodes the alpha subunit of HIF-1. Overexpression of a natural [[antisense]] transcript (aHIF) of this gene is associated with nonpapillary renal carcinomas.<ref>{{cite journal  | author=Quintero M, Mackenzie N, Brennan PA |title=Hypoxia-inducible factor 1 (HIF-1) in cancer. |journal=Eur J Surg Oncol |volume=30 |issue= 5 |pages= 465-8 |year= 2004 |pmid= 15135470 |doi= 10.1016/j.ejso.2004.03.008}}</ref> Two [[alternative splicing|alternative transcripts]] encoding different isoforms have been identified.<ref>{{cite web | title = Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3091| accessdate = }}</ref>
== Structure ==
}}


HIF1 is a [[heterodimeric]] [[basic helix-loop-helix]] structure<ref>{{cite journal | vauthors = Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT, Sun YC, Huang HC, Yang YJ, Yang KD | title = Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts | journal = J. Biol. Chem. | volume = 279 | issue = 11 | pages = 10331–7  | date = March 2004 | pmid = 14681237 | doi = 10.1074/jbc.M308013200 }}</ref> that is composed of HIF1A, the alpha subunit (this protein), and the aryl hydrocarbon receptor nuclear translocator ([[Aryl hydrocarbon receptor nuclear translocator|Arnt]]), the beta subunit. HIF1A contains a basic helix-loop-helix domain near the [[C-terminal]], followed by two distinct [[PAS domain|PAS]] (PER-ARNT-SIM) domains, and a [[PAS-associated C-terminal|PAC]] (PAS-associated C-terminal) domain.<ref name="pmid7539918" /><ref>{{cite journal | vauthors = Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA | title = Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | date = Mar 1997 | pmid = 9079689 | doi =  10.1074/jbc.272.13.8581 | pages=8581–93}}</ref> The HIF1A polypeptide also contains a nuclear localization signal motif, two transactivating domains CTAD and NTAD, and an intervening inhibitory domain (ID) that can repress the transcriptional activities of CTAD and NTAD.<ref>{{cite journal | vauthors = Jiang BH, Zheng JZ, Leung SW, Roe R, Semenza GL | title = Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension | journal = The Journal of Biological Chemistry | volume = 272 | issue = 31 | date = Aug 1997 | pmid = 9235919 | doi = 10.1074/jbc.272.31.19253| pages=19253–60}}</ref> There are a total of three HIF1A isoforms formed by alternative splicing, however isoform1 has been chosen as the canonical structure, and is the most extensively studied isoform in structure and function.<ref>{{cite journal | vauthors = Iyer NV, Leung SW, Semenza GL | title = The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation | journal = Genomics | volume = 52 | issue = 2 | date = Sep 1998 | pmid = 9782081 | doi = 10.1006/geno.1998.5416 | pages=159–65}}</ref><ref>{{Cite web|url = http://www.uniprot.org/uniprot/Q16665|title = Hypoxia-inducible factor 1-alpha|date = 2014 }}</ref>


==References==
== Gene and expression ==
{{reflist|2}}
==Further reading==


{{refbegin | 2}}
The human ''HIF1A'' gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1).<ref>{{cite web | title = HIF1A | url = https://www.ncbi.nlm.nih.gov/gene/3091 | website = National Center for Biotechnology Information}}</ref> ''HIF1A'' expression level is depedent on its GC-rich promoter activation.<ref name="Minet E 1999">{{cite journal | vauthors = Minet E, Ernest I, Michel G, Roland I, Remacle J, Raes M, Michiels C | title = HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5'UTR | journal = Biochemical and Biophysical Research Communications | volume = 261 | issue = 2 | pages = 534–40 | date = Aug 1999 | pmid = 10425220 | doi = 10.1006/bbrc.1999.0995 }}</ref> In most cells, ''HIF1A'' gene is constitutively expressed in low levels under [[wiktionary:normoxic|normoxic]] conditions, however, under [[hypoxia (medical)|hypoxia]], ''HIF1A'' transcription is often significantly upregulated.<ref name="Minet E 1999"/><ref>{{cite journal | vauthors = Danon A, Assouline G | title = Antiulcer activity of hypertonic solutions in the rat: possible role of prostaglandins | journal = European Journal of Pharmacology | volume = 58 | issue = 4 | pages = 425–431| doi = 10.1016/0014-2999(79)90313-3 }}</ref><ref>{{cite journal | vauthors = Ladoux A, Frelin C | title = Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain transcription factors involved in adaptative responses to hypoxic stresses | journal = Biochemical and Biophysical Research Communications | volume = 240 | issue = 3 | pages = 552–556 | date = Nov 1997 | pmid = 9398602 | doi = 10.1006/bbrc.1997.7708 }}</ref><ref>{{cite journal | vauthors = Wiener CM, Booth G, Semenza GL | title = In vivo expression of mRNAs encoding hypoxia-inducible factor 1 | journal = Biochemical and Biophysical Research Communications | volume = 225 | issue = 2 | pages = 485–8 | date = Aug 1996 | pmid = 8753788 | doi = 10.1006/bbrc.1996.1199 }}</ref><ref>{{cite journal | vauthors = Palmer LA, Semenza GL, Stoler MH, Johns RA | title = Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1 | journal = The American Journal of Physiology | volume = 274 | issue = 2 Pt 1 | page = L212-9 | date = Feb 1998 | pmid = 9486205 }}</ref><ref>{{cite journal | vauthors = Wenger RH, Kvietikova I, Rolfs A, Gassmann M, Marti HH | title = Hypoxia-inducible factor-1 alpha is regulated at the post-mRNA level | journal = Kidney International | volume = 51 | issue = 2 | pages = 560–563 | date = Feb 1997 | pmid = 9027739 | doi=10.1038/ki.1997.79}}</ref> Typically, oxygen-independent pathway regulates protein expression, and oxygen-dependent pathway regulates degradation.<ref name="ReferenceC">{{cite journal | vauthors = Semenza GL | title = Targeting HIF-1 for cancer therapy | journal = Nature Reviews. Cancer | volume = 3 | issue = 10 | date = Oct 2003 | pmid = 13130303 | doi = 10.1038/nrc1187 | pages=721–32}}</ref> In hypoxia-independent ways, ''HIF1A'' expression may be upregulated through a [[redox]]-sensitive mechanism.<ref>{{cite journal | vauthors = Bonello S, Zähringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, Görlach A | title = Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 27 | issue = 4 | pages = 755–761 | date = Apr 2007 | pmid = 17272744 | doi = 10.1161/01.ATV.0000258979.92828.bc }}</ref>
{{PBB_Further_reading
 
| citations =
== Function ==
*{{cite journal  | author=Semenza GL |title=HIF-1 and human disease: one highly involved factor. |journal=Genes Dev. |volume=14 |issue= 16 |pages= 1983-91 |year= 2000 |pmid= 10950862 |doi= }}
 
*{{cite journal | author=Semenza G |title=Signal transduction to hypoxia-inducible factor 1. |journal=Biochem. Pharmacol. |volume=64 |issue= 5-6 |pages= 993-8 |year= 2002 |pmid= 12213597 |doi= }}
The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals.<ref>{{cite journal | vauthors = Semenza GL | title = Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1 | journal = Annual Review of Cell and Developmental Biology | volume = 15 | pages = 551–78 | date = 1999 | pmid = 10611972 | doi = 10.1146/annurev.cellbio.15.1.551 }}</ref><ref>{{cite journal | vauthors = Semenza GL | title = HIF-1: mediator of physiological and pathophysiological responses to hypoxia | journal = Journal of Applied Physiology | volume = 88 | issue = 4 | pages = 1474–80 | date = Apr 2000 | pmid = 10749844 }}</ref> HIF1A activity is regulated by a host of [[post-translational modifications]]: [[hydroxylation]], [[acetylation]], and [[phosphorylation]].<ref>{{cite journal | vauthors = Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW | title = Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions | journal = Experimental & Molecular Medicine | volume = 36 | issue = 1 | date = Feb 2004 | pmid = 15031665 | doi = 10.1038/emm.2004.1 | pages=1–12}}</ref> HIF-1 is known to induce transcription of more than 60 genes, including [[VEGF]] and [[erythropoietin]] that are involved in biological processes such as [[angiogenesis]] and [[erythropoiesis]], which assist in promoting and increasing oxygen delivery to hypoxic regions.<ref name="Targeting HIF-1 for cancer therapy"/><ref>{{cite journal | vauthors = Semenza GL | title = HIF-1 and tumor progression: [[pathophysiology]] and therapeutics | journal = Trends in Molecular Medicine | volume = 8 | issue = 4 Suppl | page = S62-7 | date = 2002 | pmid = 11927290 | doi=10.1016/s1471-4914(02)02317-1}}</ref><ref name="ReferenceA">{{cite journal | vauthors = Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW | title = Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions | journal = Experimental & Molecular Medicine | volume = 36 | issue = 1 | pages = 1–12 | date = Feb 2004 | pmid = 15031665 | doi = 10.1038/emm.2004.1 }}</ref> HIF-1 also induces transcription of genes involved in [[cell proliferation]] and survival, as well as glucose and iron [[metabolism]].<ref name="ReferenceA"/> In accordance with its dynamic biological role, HIF-1 responds to systemic oxygen levels by undergoing conformational changes, and associates with HRE regions of promoters of hypoxia-responsive genes to induce transcription.<ref>{{cite journal | vauthors = Bruick RK, McKnight SL | title = A conserved family of prolyl-4-hydroxylases that modify HIF | journal = Science | volume = 294 | issue = 5545 | pages = 1337–40 | date = Nov 2001 | pmid = 11598268 | doi = 10.1126/science.1066373 }}</ref><ref name="ReferenceB">{{cite journal | vauthors = Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ | title = C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation | journal = Cell | volume = 107 | issue = 1 | pages = 43–54 | date = Oct 2001 | pmid = 11595184 | doi=10.1016/s0092-8674(01)00507-4}}</ref><ref>{{cite journal | vauthors = Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG | title = HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing | journal = Science | volume = 292 | issue = 5516 | pages = 464–8 | date = Apr 2001 | pmid = 11292862 | doi = 10.1126/science.1059817 }}</ref><ref>{{cite journal | vauthors = Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ | title = Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation | journal = Science | volume = 292 | issue = 5516 | pages = 468–72 | date = Apr 2001 | pmid = 11292861 | doi = 10.1126/science.1059796 }}</ref><ref>{{cite journal | vauthors = Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ | title = Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation | journal = The EMBO Journal | volume = 20 | issue = 18 | pages = 5197–206 | date = Sep 2001 | pmid = 11566883 | doi = 10.1093/emboj/20.18.5197 | pmc=125617}}</ref> HIF1A stability, subcellular localization, as well as transcriptional activity are especially affected by oxygen level. The alpha subunit forms a heterodimer with the beta subunit. Under [[normoxic]] conditions, VHL-mediated ubiquitin protease pathway rapidly degrades HIF1a; however, under hypoxia, HIF1A [[protein degradation]] is prevented and HIF1A levels accumulate to associate with HIF1B to exert transcriptional roles on target genes <ref>{{cite journal | vauthors = Huang LE, Arany Z, Livingston DM, Bunn HF | title = Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit | journal = The Journal of Biological Chemistry | volume = 271 | issue = 50 | pages = 32253–9 | date = Dec 1996 | pmid = 8943284 | doi=10.1074/jbc.271.50.32253}}</ref><ref>{{cite journal | vauthors = Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L | title = Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 11 | pages = 5667–72 | date = May 1997 | pmid = 9159130 | doi=10.1073/pnas.94.11.5667 | pmc=20836}}</ref> Enzymes [[prolyl hydroxylase]] (PHD) and HIF prolyl hydroxylase (HPH) are involved in specific post-translational modification of HIF1A proline residues  (P402 and P564 within the ODD domain), which allows for VHL association with HIF1A.<ref>{{cite journal | vauthors = Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ | title = Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation | journal = The EMBO Journal | volume = 20 | issue = 18 | pages = 5197–206 | date = Sep 2001 | pmid = 11566883 | doi = 10.1093/emboj/20.18.5197 | pmc=125617}}</ref> The enzymatic activity of oxygen sensor [[dioxygenase]] PHD is dependent on oxygen level as it requires oxygen as one of its main substrates to transfer to the [[proline]] residue of HIF1A.<ref name="ReferenceB"/><ref>{{cite journal | vauthors = Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M | title = Induction of HIF-1alpha in response to hypoxia is instantaneous | journal = FASEB Journal | volume = 15 | issue = 7 | pages = 1312–4 | date = May 2001 | pmid = 11344124 | doi=10.1096/fj.00-0732fje}}</ref> The hydroxylated proline residue of HIF1A is then recognized and buried in the [[hydrophobic core]] of [[von Hippel-Lindau]] [[tumor suppressor]] protein (VHL), which itself is part of a [[ubiquitin ligase]] [[enzyme]].<ref>{{cite journal | vauthors = Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, Maxwell PH, Ratcliffe PJ, Stuart DI, Jones EY | title = Structural basis for the recognition of hydroxyproline in HIF-1 alpha by VHL | journal = Nature | volume = 417 | issue = 6892 | pages = 975–8 | date = Jun 2002 | pmid = 12050673 | doi = 10.1038/nature00767 }}</ref><ref>{{cite journal | vauthors = Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich NP | title = Structure of an HIF-1alpha -VHL complex: hydroxyproline recognition in signaling | journal = Science | volume = 296 | issue = 5574 | pages = 1886–9 | date = Jun 2002 | pmid = 12004076 | doi = 10.1126/science.1073440 }}</ref> The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia.<ref>{{cite journal | vauthors = Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML | title = Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch | journal = Science | volume = 295 | issue = 5556 | pages = 858–61 | date = Feb 2002 | pmid = 11823643 | doi = 10.1126/science.1068592 }}</ref><ref>{{cite journal | vauthors = Sang N, Fang J, Srinivas V, Leshchinsky I, Caro J | title = Carboxyl-terminal transactivation activity of hypoxia-inducible factor 1 alpha is governed by a von Hippel-Lindau protein-independent, hydroxylation-regulated association with p300/CBP | journal = Molecular and Cellular Biology | volume = 22 | issue = 9 | pages = 2984–92 | date = May 2002 | pmid = 11940656 | doi=10.1128/mcb.22.9.2984-2992.2002 | pmc=133771}}</ref> Function of HIF1A gene can be effectively examined by siRNA knockdown based on an independent validation.<ref>{{Cite journal|last=Munkácsy|first=Gyöngyi|last2=Sztupinszki|first2=Zsófia|last3=Herman|first3=Péter|last4=Bán|first4=Bence|last5=Pénzváltó|first5=Zsófia|last6=Szarvas|first6=Nóra|last7=Győrffy|first7=Balázs|date=2016|title=Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments|url=http://www.cell.com/molecular-therapy-family/nucleic-acids/abstract/S2162-2531(17)30085-9|journal=Molecular Therapy - Nucleic Acids|language=English|volume=5|doi=10.1038/mtna.2016.66|issn=2162-2531|pmc=5056990|pmid=28131298}}</ref>
*{{cite journal | author=Arbeit JM |title=Quiescent hypervascularity mediated by gain of HIF-1 alpha function. |journal=Cold Spring Harb. Symp. Quant. Biol. |volume=67 |issue= |pages= 133-42 |year= 2003 |pmid= 12858534 |doi= }}
 
*{{cite journal | author=Sitkovsky M, Lukashev D |title=Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. |journal=Nat. Rev. Immunol. |volume=5 |issue= 9 |pages= 712-21 |year= 2005 |pmid= 16110315 |doi= 10.1038/nri1685 }}
=== Repair and regeneration ===
*{{cite journal | author=Mobasheri A, Richardson S, Mobasheri R, ''et al.'' |title=Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes. |journal=Histol. Histopathol. |volume=20 |issue= 4 |pages= 1327-38 |year= 2006 |pmid= 16136514 |doi=  }}
 
*{{cite journal | author=Schipani E |title=Hypoxia and HIF-1 alpha in chondrogenesis. |journal=Semin. Cell Dev. Biol. |volume=16 |issue= 4-5 |pages= 539-46 |year= 2006 |pmid= 16144691 |doi= 10.1016/j.semcdb.2005.03.003 }}
In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF1A via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of HIF1A results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF1A can either turn off, or turn on the key processes of mammalian regeneration.<ref name=HIF-1a2015>{{cite web| last = eurekalert.org staff | title = Scientist at LIMR leads study demonstrating drug-induced tissue regeneration | website = eurekalert.org | publisher = Lankenau Institute for Medical Research (LIMR), | date = 3 June 2015 | url = http://www.eurekalert.org/pub_releases/2015-06/mlhl-sal060215.php | accessdate = 3 July 2015 | archiveurl =  | archivedate = }}</ref><ref name=HIFregulation2015>{{cite journal | vauthors = Zhang Y, Strehin I, Bedelbaeva K, Gourevitch D, Clark L, Leferovich J, Messersmith PB, Heber-Katz E | year = 2015 | title = Drug-induced regeneration in adult mice | url = | journal = Sci Transl Med | volume = 290 | issue = | page = }}</ref>
*{{cite journal | author=Haase VH |title=Hypoxia-inducible factors in the kidney. |journal=Am. J. Physiol. Renal Physiol. |volume=291 |issue= 2 |pages= F271-81 |year= 2006 |pmid= 16554418 |doi= 10.1152/ajprenal.00071.2006 }}
 
*{{cite journal | author=Liang D, Kong X, Sang N |title=Effects of histone deacetylase inhibitors on HIF-1. |journal=Cell Cycle |volume=5 |issue= 21 |pages= 2430-5 |year= 2007 |pmid= 17102633 |doi= }}
== Regulation ==
}}
 
HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an [[NF-κB]]-dependent manner.<ref name="pmid18393939">{{cite journal | vauthors = van Uden P, Kenneth NS, Rocha S | title = Regulation of hypoxia-inducible factor-1alpha by NF-kappaB | journal = Biochem. J. | volume = 412 | issue = 3 | pages = 477–84 | year = 2008 | pmid = 18393939 | pmc = 2474706 | doi = 10.1042/BJ20080476 | url = http://www.hif1.com }}</ref> In addition, the coordinated activity of the [[prolyl hydroxylase]]s (PHDs) maintain the appropriate balance of HIF1A protein in the post-translation phase.<ref name="pmid15304631">{{cite journal | vauthors = Semenza GL | title = Hydroxylation of HIF-1: oxygen sensing at the molecular level | journal = Physiology (Bethesda) | volume = 19 | issue = 4 | pages = 176–82  | date = August 2004 | pmid = 15304631 | doi = 10.1152/physiol.00001.2004 }}</ref>
 
PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as [[desferrioxamine]] (DFO) have proven successful in HIF1A stabilization.<ref name="Xiao_2013">{{cite journal | vauthors = Xiao H, Gu Z, Wang G, Zhao T | title = The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain therapies | journal = Int J Med Sci | volume = 10 | issue = 10 | pages = 1412–21 | year = 2013 | pmid = 23983604 | pmc = 3752727 | doi = 10.7150/ijms.5630 }}</ref> HBO (Hyperbaric oxygen therapy) and HIF1A imitators such as cobalt chloride have also been successfully utilized.<ref name="Xiao_2013"/>
 
Factors increasing HIF1A<ref name="pmid18809331">{{cite journal | vauthors = Yee Koh M, Spivak-Kroizman TR, Powis G | title = HIF-1 regulation: not so easy come, easy go | journal = Trends Biochem. Sci. | volume = 33 | issue = 11 | pages = 526–34  | date = November 2008 | pmid = 18809331 | doi = 10.1016/j.tibs.2008.08.002 }}</ref>
{{div col|colwidth=20em}}
 
*  Modulator of Degradation:
** Oxygen-Dependent:
*** [[UBE2S|EPF UCP]] (degrades pHVL)
*** [[USP20|VDU2]]  (de-ubiquitinates HIF1A)
*** [[SUMO protein|SUMOylation]] (via [[RWDD3|RSUME]])
*** DeSUMOylation ( via [[SENP1]])
** Oxygen-independent:
*** [[Calcineurin|Calcineurin A]] ( Ca2+-dependent via [[GNB2L1|RACK1]])
* Modulators of translation:
** RNA-binding proteins, [[PTBP1|PTB]], and [[ELAVL1|HuR]]
** [[PtdIns3K]] and [[MAPK/ERK pathway|MAPK]] pathways
** [[Internal ribosome entry site|IRES]]-mediated translation
** calcium signaling
** [[miRNA]]s
{{Div col end}}
 
Factors decreasing HIF1A<ref name="pmid18809331"/>
{{div col|colwidth=20em}}
*  Modulator of Degradation:
** Oxygen-Dependent:
*** [[Prolyl hydroxylase|PHD]], [[Von Hippel–Lindau tumor suppressor|VHL]], [[OS-9]] and [[SAT2|SSAT2]]
*** SUMOylation
** Oxygen-independent
*** [[RACK1]] and [[SAT1 (gene)|SSAT1]]
*** [[GSK3B|GSK3β]]
*** [[FOXO4]]
*Modulators of translation:
** Calcium signaling
** miRNAs
{{Div col end}}
 
== Role in cancer ==
 
HIF-1 is overexpressed in many human cancers.<ref>{{cite journal | vauthors = Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW | title = Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their [[metastases]] | journal = Cancer Research | volume = 59 | issue = 22 | date = Nov 1999 | pmid = 10582706 | doi = | pages=5830–5}}</ref><ref>{{cite journal | vauthors = Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL | title = The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages | journal = The American Journal of Pathology | volume = 157 | issue = 2 | date = Aug 2000 | pmid = 10934146 | doi = 10.1016/s0002-9440(10)64554-3| pages=411–21 | pmc=1850121}}</ref> HIF-1 overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia.<ref>{{cite journal | vauthors = Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E | title = Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma | journal = Cancer | volume = 97 | issue = 6 | date = Mar 2003 | pmid = 12627523 | doi = 10.1002/cncr.11246 | pages=1573–81}}</ref> Hypoxia promotes apoptosis in both normal and tumor cells.<ref>{{cite journal | vauthors = Vaupel P, Mayer A | title = Hypoxia in cancer: significance and impact on clinical outcome | journal = Cancer Metastasis Reviews | volume = 26 | issue = 2 | date = Jun 2007 | pmid = 17440684 | doi = 10.1007/s10555-007-9055-1 | pages=225–39}}</ref> However, hypoxic conditions in [[tumor microenvironment]] especially, along with accumulation of genetic alternations often contribute to ''HIF-1'' overexpression.<ref name="Targeting HIF-1 for cancer therapy"/>
 
Significant HIF-1 expression has been noted in most solid tumors studied, which include cancers of the [[Large intestine|colon]], [[breast]], [[pancreas]], [[kidneys]], [[prostate]], [[ovary]], [[brain]], and [[bladder]].<ref>{{cite journal | vauthors = Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL | title = The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages | journal = The American Journal of Pathology | volume = 157 | issue = 2 | date = Aug 2000 | pmid = 10934146 | doi = 10.1016/s0002-9440(10)64554-3| pages=411–21 | pmc=1850121}}</ref><ref>{{cite journal | vauthors = Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW | title = Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases | journal = Cancer Research | volume = 59 | issue = 22 | date = Nov 1999 | pmid = 10582706 | doi = | pages=5830–5}}</ref> Clinically, elevated Hif-1a levels in a number of cancers, including [[cervical cancer]], [[non-small-cell lung carcinoma]], [[breast cancer]] (LV-positive and negative), [[oligodendroglioma]], [[oropharyngeal cancer]], [[ovarian cancer]], [[endometrial cancer]], [[esophageal cancer]], [[head and neck cancer]], and [[stomach cancer]], have been associated with aggressive tumor progression, and thus has been implicated as a predictive and prognostic marker for resistance to [[radiation treatment]], [[chemotherapy]], and increased mortality.<ref name="ReferenceC"/><ref>{{cite journal | vauthors = Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL | title = Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer | journal = Cancer Research | volume = 61 | issue = 7 | date = Apr 2001 | pmid = 11306467 | doi = | pages=2911–6}}</ref><ref>{{cite journal | vauthors = Höckel M, Vaupel P | title = Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects | journal = Journal of the National Cancer Institute | volume = 93 | issue = 4 | date = Feb 2001 | pmid = 11181773 | doi = 10.1093/jnci/93.4.266| pages=266–76}}</ref><ref>{{cite journal | vauthors = Dvorák K | title = Intravenous systemic thrombolysis using streptokinase in the treatment of developing cardiogenic shock in myocardial infarct | language = Czech | journal = Vnitr̆ní Lékar̆ství | volume = 36 | issue = 5 | date = May 1990 | pmid = 2375073 | doi = | pages=426–34}}</ref><ref>{{cite journal | vauthors = Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G | title = Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy | journal = Clinical Cancer Research | volume = 7 | issue = 6 | date = Jun 2001 | pmid = 11410504 | doi = | pages=1661–8}}</ref><ref>{{cite journal | vauthors = Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E | title = Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma | journal = Cancer | volume = 97 | issue = 6 | date = Mar 2003 | pmid = 12627523 | doi = 10.1002/cncr.11246 | pages=1573–81}}</ref><ref>{{cite journal | vauthors = Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL | title = Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer | journal = Cancer Research | volume = 61 | issue = 7 | date = Apr 2001 | pmid = 11306467 | doi = | pages=2911–6}}</ref>
 
HIF1A expression may also regulate breast [[tumor progression]]. Elevated HIF1A levels may be detected in early cancer development, and have been found in early [[ductal carcinoma in situ|ductal carcinoma ''in situ'']], a pre-invasive stage in breast cancer development, and is also  associated with increased [[microvasculature]] density in tumor [[lesions]].<ref>{{cite journal | vauthors = Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E | title = Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis | journal = Journal of the National Cancer Institute | volume = 93 | issue = 4 | pages = 309–14 | date = Feb 2001 | pmid = 11181778 | doi = 10.1093/jnci/93.4.309}}</ref>  Moreover, despite histologically-determined low-grade, lymph-node negative breast tumor in a subset of patients examined, detection of significant HIF1A expression was able to independently predict poor response to therapy.<ref>{{cite journal | vauthors = Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E | title = Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma | journal = Cancer | volume = 97 | issue = 6 | date = Mar 2003 | pmid = 12627523 | doi = 10.1002/cncr.11246 | pages=1573–81}}</ref> Similar findings have been reported in brain cancer and ovarian cancer studies as  well, and suggest at regulatory role of HIF1A in initiating [[angiogenesis]] through interactions with pro-angiogenic factors such as [[VEGF]].<ref>{{cite journal | vauthors = Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G | title = Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy | journal = Clinical Cancer Research | volume = 7 | issue = 6 | date = Jun 2001 | pmid = 11410504 | doi = | pages=1661–8}}</ref><ref name=":0">{{cite journal | vauthors = Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL | title = Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression | journal = Cancer | volume = 88 | issue = 11 | date = Jun 2000 | pmid = 10861440 | doi = 10.1002/1097-0142(20000601)88:11<2606::aid-cncr25>3.0.co;2-w| pages=2606–18}}</ref> Studies of [[glioblastoma multiforme]] show striking similarity between HIF1A expression pattern and that of [[VEGF]] [[gene transcription]] level.<ref>{{cite journal | vauthors = Neufeld G, Kessler O, Vadasz Z, Gluzman-Poltorak Z | title = The contribution of proangiogenic factors to the progression of [[malignant]] disease: role of vascular endothelial growth factor and its receptors | journal = Surgical Oncology Clinics of North America | volume = 10 | issue = 2 | date = Apr 2001 | pmid = 11382591 | doi = | pages=339–56, ix}}</ref><ref>{{cite journal | vauthors = Powis G, Kirkpatrick L | title = Hypoxia inducible factor-1alpha as a cancer drug target | journal = Molecular Cancer Therapeutics | volume = 3 | issue = 5 | date = May 2004 | pmid = 15141023 | doi = | pages=647–54}}</ref> In addition, high-grade glioblastoma multiform tumors with high VEGF expression pattern, similar to breast cancer with HIF1A overexpression, display significant signs of tumor [[neovascularization]].<ref>{{cite journal | vauthors = Pietsch T, Valter MM, Wolf HK, von Deimling A, Huang HJ, Cavenee WK, Wiestler OD | title = Expression and distribution of vascular endothelial growth factor protein in human brain tumors | journal = Acta Neuropathologica | volume = 93 | issue = 2 | date = Feb 1997 | pmid = 9039457 | doi = 10.1007/s004010050591| pages=109–17}}</ref> This further suggests the regulatory role of HIF1A in promoting tumor progression, likely through hypoxia-induced VEGF expression pathways.<ref>{{cite journal | vauthors = Powis G, Kirkpatrick L | title = Hypoxia inducible factor-1alpha as a cancer drug target | journal = Molecular Cancer Therapeutics | volume = 3 | issue = 5 | date = May 2004 | pmid = 15141023 | doi = | pages=647–54}}</ref>
 
HIF1A overexpression in tumors may also occur in a hypoxia-independent pathway. In hemagioblastoma, HIF1A expression is found in most cells sampled from the well-vascularized tumor.<ref name=":1">{{cite journal | vauthors = Krieg M, Haas R, Brauch H, Acker T, Flamme I, Plate KH | title = Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function | journal = Oncogene | volume = 19 | issue = 48 | date = Nov 2000 | pmid = 11114720 | doi = 10.1038/sj.onc.1203938 | pages=5435–43}}</ref> Although in both renal carcinoma and hemagioblastoma, the von Hippel-Lindau gene is inactivated, HIF1A is still expressed at high levels.<ref name=":0" /><ref name=":1" /><ref>{{cite journal | vauthors = Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW | title = Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases | journal = Cancer Research | volume = 59 | issue = 22 | date = Nov 1999 | pmid = 10582706 | doi = | pages=5830–5}}</ref> In addition to VEGF overexpression in response elevated HIF1A levels, the [[PI3K]]/[[AKT]] pathway is also involved in tumor growth. In prostate cancers, the commonly occurring [[PTEN (gene)|PTEN]] mutation is associated with tumor progression toward aggressive stage, increased vascular density and angiogenesis.<ref>{{cite journal | vauthors = Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ | title = Loss of PTEN facilitates HIF-1-mediated gene expression | journal = Genes & Development | volume = 14 | issue = 4 | date = Feb 2000 | pmid = 10691731 | doi = | pages=391–6 | pmc=316386}}</ref>
 
During hypoxia, [[tumor suppressor]] [[p53]] overexpression may be associated with HIF1A-dependent pathway to initiate apoptosis. Moreover, p53-independent pathway may also induce apoptosis through the [[Bcl-2]] pathway.<ref>{{cite journal | vauthors = Vaupel P, Mayer A | title = Hypoxia in cancer: significance and impact on clinical outcome | journal = Cancer Metastasis Reviews | volume = 26 | issue = 2 | date = Jun 2007 | pmid = 17440684 | doi = 10.1007/s10555-007-9055-1 | pages=225–39}}</ref> However, overexpression of HIF1A is cancer- and individual-specific, and depends on the accompanying genetic alternations and levels of pro- and anti-apoptotic factors present. One study on epithelial ovarian cancer shows HIF1A and nonfunctional tumor suppressor [[p53]]  is correlated with low levels of tumor cell apoptosis and poor prognosis.<ref>{{cite journal | vauthors = Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G | title = Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on [[prognosis]] and on response to chemotherapy | journal = Clinical Cancer Research | volume = 7 | issue = 6 | pages = 1661–8 | date = Jun 2001 | pmid = 11410504 }}</ref>  Further, early-stage esophageal cancer patients with demonstrated overexpression of HIF1 and absence of BCL2 expression also failed photodynamic therapy.<ref>{{cite journal | vauthors = Koukourakis MI, Giatromanolaki A, Skarlatos J, Corti L, Blandamura S, Piazza M, Gatter KC, Harris AL | title = Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy | journal = Cancer Research | volume = 61 | issue = 5 | pages = 1830–2 | date = Mar 2001 | pmid = 11280732 }}</ref> Studies of glioblastoma multiforme show striking similarity between HIF1A protein expression pattern and that of VEGF gene transcription level.
 
While research efforts to develop therapeutic drugs to target hypoxia-associated tumor cells have been ongoing for many years, there has not yet been any breakthrough that has shown selectivity and effectiveness at targeting HIF1A pathways to decrease tumor progression and angiogenesis.<ref>{{Cite journal|title = Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma|last = Liu|first = X|date = 2014|journal = Autophagy|doi = 10.4161/auto.26838|pmid = 24220190|volume=10|pages=111–22|pmc=4389865}}</ref> Successful therapeutic approaches in the future may also be highly case-specific to particular cancers ad individuals, and seem unlikely to be widely applicable due to the genetically [[heterogenous]] nature of the many cancer types and subtypes.
 
== Interactions ==
 
HIF1A has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[ARNTL]],<ref name = pmid9576906>{{cite journal | vauthors = Hogenesch JB, Gu YZ, Jain S, Bradfield CA | title = The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 10 | pages = 5474–9  | date = May 1998 | pmid = 9576906 | pmc = 20401 | doi = 10.1073/pnas.95.10.5474 }}</ref>
* [[Aryl hydrocarbon receptor nuclear translocator|ARNT]],<ref name = pmid9079689 /><ref name = pmid11782478>{{cite journal | vauthors = Woods SL, Whitelaw ML | title = Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors | journal = J. Biol. Chem. | volume = 277 | issue = 12 | pages = 10236–43  | date = Mar 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 }}</ref>
* [[CREB binding protein|CREBB]],<ref name = pmid10202154>{{cite journal | vauthors = Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y | title = Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300 | journal = EMBO J. | volume = 18 | issue = 7 | pages = 1905–14  | date = Apr 1999 | pmid = 10202154 | pmc = 1171276 | doi = 10.1093/emboj/18.7.1905 }}</ref><ref name = pmid9887100>{{cite journal | vauthors = Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM | title = Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1 | journal = Genes Dev. | volume = 13 | issue = 1 | pages = 64–75  | date = Jan 1999 | pmid = 9887100 | pmc = 316375 | doi = 10.1101/gad.13.1.64 }}</ref><ref name = pmid18426857>{{cite journal | vauthors = Park YK, Ahn DR, Oh M, Lee T, Yang EG, Son M, Park H | title = Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel-Lindau recruitment and asparagine hydroxylation | journal = Mol. Pharmacol. | volume = 74 | issue = 1 | pages = 236–45  | date = Jul 2008 | pmid = 18426857 | doi = 10.1124/mol.108.045278 }}</ref>
* [[EP300]],<ref name = pmid11823643>{{cite journal | vauthors = Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML | title = Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch | journal = Science | volume = 295 | issue = 5556 | pages = 858–61  | date = Feb 2002 | pmid = 11823643 | doi = 10.1126/science.1068592 }}</ref><ref name = pmid11959990>{{cite journal | vauthors = Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ | title = Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 8 | pages = 5367–72  | date = Apr 2002 | pmid = 11959990 | pmc = 122775 | doi = 10.1073/pnas.082117899 }}</ref>
* [[HIF1AN]],<ref name = pmid11641274>{{cite journal | vauthors = Mahon PC, Hirota K, Semenza GL | title = FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity | journal = Genes Dev. | volume = 15 | issue = 20 | pages = 2675–86  | date = Oct 2001 | pmid = 11641274 | pmc = 312814 | doi = 10.1101/gad.924501 }}</ref>
* [[Mdm2]],<ref name = pmid12606552/><ref name = pmid10640274/>
* [[Nerve Growth factor IB|NR4A]],<ref name = pmid18305400>{{cite journal | vauthors = Kim BY, Kim H, Cho EJ, Youn HD | title = Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation | journal = Exp. Mol. Med. | volume = 40 | issue = 1 | pages = 71–83  | date = Feb 2008 | pmid = 18305400 | pmc = 2679322 | doi = 10.3858/emm.2008.40.1.71 }}</ref>
* [[P53]],<ref name = pmid12606552>{{cite journal | vauthors = Chen D, Li M, Luo J, Gu W | title = Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function | journal = J. Biol. Chem. | volume = 278 | issue = 16 | pages = 13595–8  | date = Apr 2003 | pmid = 12606552 | doi = 10.1074/jbc.C200694200 }}</ref><ref name = pmid10640274>{{cite journal | vauthors = Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A | title = Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha | journal = Genes Dev. | volume = 14 | issue = 1 | pages = 34–44  | date = Jan 2000 | pmid = 10640274 | pmc = 316350 | doi =  10.1101/gad.14.1.34}}</ref><ref name = pmid12124396>{{cite journal | vauthors = Hansson LO, Friedler A, Freund S, Rudiger S, Fersht AR | title = Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 16 | pages = 10305–9  | date = Aug 2002 | pmid = 12124396 | pmc = 124909 | doi = 10.1073/pnas.122347199 }}</ref><ref name = pmid9537326>{{cite journal | vauthors = An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM | title = Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha | journal = Nature | volume = 392 | issue = 6674 | pages = 405–8  | date = Mar 1998 | pmid = 9537326 | doi = 10.1038/32925 }}</ref>
* [[PSMA7]],<ref name = pmid11389899>{{cite journal | vauthors = Cho S, Choi YJ, Kim JM, Jeong ST, Kim JH, Kim SH, Ryu SE | title = Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7 | journal = FEBS Lett. | volume = 498 | issue = 1 | pages = 62–6  | date = Jun 2001 | pmid = 11389899 | doi = 10.1016/S0014-5793(01)02499-1 }}</ref>
* [[STAT3]],<ref name = pmid18985005>{{cite journal | vauthors = Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH, Kim TY, Juhnn YS, Kim SJ, Park JW, Ye SK, Chung MH | title = STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination | journal = Exp. Mol. Med. | volume = 40 | issue = 5 | pages = 479–85  | date = Oct 2008 | pmid = 18985005 | pmc = 2679355 | doi = 10.3858/emm.2008.40.5.479 }}</ref>
* [[Ubiquitin C|UBC]],<ref name = pmid18426857/><ref name = pmid18305400/><ref name = pmid18694926/>
* [[Von Hippel-Lindau tumor suppressor|VH]]<ref name = pmid18426857/><ref name = pmid11641274/><ref name = pmid18305400/><ref name = pmid18985005/><ref name = pmid18694926>{{cite journal | vauthors = André H, Pereira TS | title = Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha | journal = J. Biol. Chem. | volume = 283 | issue = 43 | pages = 29375–84  | date = Oct 2008 | pmid = 18694926 | pmc = 2662024 | doi = 10.1074/jbc.M805919200 }}</ref><ref name = pmid14556007>{{cite journal | vauthors = Corn PG, McDonald ER, Herman JG, El-Deiry WS | title = Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein | journal = Nat. Genet. | volume = 35 | issue = 3 | pages = 229–37  | date = Nov 2003 | pmid = 14556007 | doi = 10.1038/ng1254 }}</ref><ref name = pmid12682018>{{cite journal | vauthors = Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G | title = The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity | journal = EMBO J. | volume = 22 | issue = 8 | pages = 1857–67  | date = Apr 2003 | pmid = 12682018 | pmc = 154465 | doi = 10.1093/emboj/cdg173 }}</ref><ref name = pmid10944113>{{cite journal | vauthors = Tanimoto K, Makino Y, Pereira T, Poellinger L | title = Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein | journal = EMBO J. | volume = 19 | issue = 16 | pages = 4298–309  | date = Aug 2000 | pmid = 10944113 | pmc = 302039 | doi = 10.1093/emboj/19.16.4298 }}</ref><ref name = pmid12004076>{{cite journal | vauthors = Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich NP | title = Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling | journal = Science | volume = 296 | issue = 5574 | pages = 1886–9  | date = Jun 2002 | pmid = 12004076 | doi = 10.1126/science.1073440 }}</ref><ref name = pmid11504942>{{cite journal | vauthors = Yu F, White SB, Zhao Q, Lee FS | title = HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 17 | pages = 9630–5  | date = Aug 2001 | pmid = 11504942 | pmc = 55503 | doi = 10.1073/pnas.181341498 }}</ref>  and
* [[Von Hippel–Lindau tumor suppressor|VHL]].<ref name = "pmid19671042">{{cite journal | vauthors = Haase VH | title = The VHL tumor suppressor: master regulator of HIF | journal = Curr. Pharm. Des. | volume = 15 | issue = 33 | pages = 3895–903 | year = 2009 | pmid = 19671042 | pmc = 3622710 | doi = 10.2174/138161209789649394 }}</ref>
* [[Glucocorticoid receptor|GR (NR3C1)]].<ref name = "pmid20631191">{{cite journal | vauthors = Sun YY | title = Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1alpha in a cell-type-specific manner. | journal = J Neurosci | volume = 30 | issue = 28 | pages = 9621–30 | year = 2010 | pmid = 20631191 | doi = 10.1523/JNEUROSCI.2295-10.2010 }}</ref><ref>{{cite journal |doi=10.1016/j.yhbeh.2016.11.013 |title=Anoxia ameliorates the dexamethasone-induced neurobehavioral alterations in the neonatal male rat pups |journal=Horm Behav |volume=87 |pages=122–128 |year=2017 | pmid = 27865789 |last1=Menshanov |first1=Petr N |last2=Bannova |first2=Anita V |last3=Dygalo |first3=Nikolay N}}</ref>
{{Div col end}}
 
== See also ==
* [[Hypoxia inducible factors]]
 
== References ==
{{Reflist|colwidth=33em}}
 
== Further reading ==
{{refbegin|colwidth=33em}}
* {{cite journal | vauthors = Semenza GL | title = HIF-1 and human disease: one highly involved factor | journal = Genes Dev. | volume = 14 | issue = 16 | pages = 1983–91 | year = 2000 | pmid = 10950862 | doi =  }}
* {{cite journal | vauthors = Semenza G | title = Signal transduction to hypoxia-inducible factor 1 | journal = Biochem. Pharmacol. | volume = 64 | issue = 5–6 | pages = 993–8 | year = 2002 | pmid = 12213597 | doi = 10.1016/S0006-2952(02)01168-1 }}
* {{cite journal | vauthors = Arbeit JM | title = Quiescent hypervascularity mediated by gain of HIF-1 alpha function | journal = Cold Spring Harb. Symp. Quant. Biol. | volume = 67 | issue =  | pages = 133–42 | year = 2002 | pmid = 12858534 | doi = 10.1101/sqb.2002.67.133 }}
* {{cite journal | vauthors = Sitkovsky M, Lukashev D | title = Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors | journal = Nat. Rev. Immunol. | volume = 5 | issue = 9 | pages = 712–21 | year = 2005 | pmid = 16110315 | doi = 10.1038/nri1685 }}
* {{cite journal | vauthors = Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland JA | title = Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes | journal = Histol. Histopathol. | volume = 20 | issue = 4 | pages = 1327–38 | year = 2005 | pmid = 16136514 | doi =  }}
* {{cite journal | vauthors = Schipani E | title = Hypoxia and HIF-1 alpha in chondrogenesis | journal = Semin. Cell Dev. Biol. | volume = 16 | issue = 4–5 | pages = 539–46 | year = 2006 | pmid = 16144691 | doi = 10.1016/j.semcdb.2005.03.003 }}
* {{cite journal | vauthors = Haase VH | title = Hypoxia-inducible factors in the kidney | journal = Am. J. Physiol. Renal Physiol. | volume = 291 | issue = 2 | pages = F271-81 | year = 2006 | pmid = 16554418 | doi = 10.1152/ajprenal.00071.2006 }}
* {{cite journal | vauthors = Liang D, Kong X, Sang N | title = Effects of histone deacetylase inhibitors on HIF-1 | journal = Cell Cycle | volume = 5 | issue = 21 | pages = 2430–5 | year = 2006 | pmid = 17102633 | doi = 10.4161/cc.5.21.3409 }}
{{refend}}
{{refend}}


{{Protein-stub}}
{{PDB Gallery|geneid=3091}}
 
{{Transcription factors|g1}}


{{WikiDoc Sources}}
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[[Category:Transcription factors]]
[[Category:PAS-domain-containing proteins]]

Revision as of 13:36, 31 August 2017

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Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene.[1][2][3] It is a basic helix-loop-helix PAS domain containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia.[4][5] The dysregulation and overexpression of HIF1A by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion.[3][6] Two other alternative transcripts encoding different isoforms have been identified.[3]

Structure

HIF1 is a heterodimeric basic helix-loop-helix structure[7] that is composed of HIF1A, the alpha subunit (this protein), and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit. HIF1A contains a basic helix-loop-helix domain near the C-terminal, followed by two distinct PAS (PER-ARNT-SIM) domains, and a PAC (PAS-associated C-terminal) domain.[4][8] The HIF1A polypeptide also contains a nuclear localization signal motif, two transactivating domains CTAD and NTAD, and an intervening inhibitory domain (ID) that can repress the transcriptional activities of CTAD and NTAD.[9] There are a total of three HIF1A isoforms formed by alternative splicing, however isoform1 has been chosen as the canonical structure, and is the most extensively studied isoform in structure and function.[10][11]

Gene and expression

The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1).[12] HIF1A expression level is depedent on its GC-rich promoter activation.[13] In most cells, HIF1A gene is constitutively expressed in low levels under normoxic conditions, however, under hypoxia, HIF1A transcription is often significantly upregulated.[13][14][15][16][17][18] Typically, oxygen-independent pathway regulates protein expression, and oxygen-dependent pathway regulates degradation.[19] In hypoxia-independent ways, HIF1A expression may be upregulated through a redox-sensitive mechanism.[20]

Function

The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals.[21][22] HIF1A activity is regulated by a host of post-translational modifications: hydroxylation, acetylation, and phosphorylation.[23] HIF-1 is known to induce transcription of more than 60 genes, including VEGF and erythropoietin that are involved in biological processes such as angiogenesis and erythropoiesis, which assist in promoting and increasing oxygen delivery to hypoxic regions.[6][24][25] HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism.[25] In accordance with its dynamic biological role, HIF-1 responds to systemic oxygen levels by undergoing conformational changes, and associates with HRE regions of promoters of hypoxia-responsive genes to induce transcription.[26][27][28][29][30] HIF1A stability, subcellular localization, as well as transcriptional activity are especially affected by oxygen level. The alpha subunit forms a heterodimer with the beta subunit. Under normoxic conditions, VHL-mediated ubiquitin protease pathway rapidly degrades HIF1a; however, under hypoxia, HIF1A protein degradation is prevented and HIF1A levels accumulate to associate with HIF1B to exert transcriptional roles on target genes [31][32] Enzymes prolyl hydroxylase (PHD) and HIF prolyl hydroxylase (HPH) are involved in specific post-translational modification of HIF1A proline residues (P402 and P564 within the ODD domain), which allows for VHL association with HIF1A.[33] The enzymatic activity of oxygen sensor dioxygenase PHD is dependent on oxygen level as it requires oxygen as one of its main substrates to transfer to the proline residue of HIF1A.[27][34] The hydroxylated proline residue of HIF1A is then recognized and buried in the hydrophobic core of von Hippel-Lindau tumor suppressor protein (VHL), which itself is part of a ubiquitin ligase enzyme.[35][36] The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia.[37][38] Function of HIF1A gene can be effectively examined by siRNA knockdown based on an independent validation.[39]

Repair and regeneration

In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF1A via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of HIF1A results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF1A can either turn off, or turn on the key processes of mammalian regeneration.[40][41]

Regulation

HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an NF-κB-dependent manner.[42] In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF1A protein in the post-translation phase.[43]

PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as desferrioxamine (DFO) have proven successful in HIF1A stabilization.[44] HBO (Hyperbaric oxygen therapy) and HIF1A imitators such as cobalt chloride have also been successfully utilized.[44]

Factors increasing HIF1A[45]

Factors decreasing HIF1A[45]

  • Modulator of Degradation:
  • Modulators of translation:
    • Calcium signaling
    • miRNAs

Role in cancer

HIF-1 is overexpressed in many human cancers.[46][47] HIF-1 overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia.[48] Hypoxia promotes apoptosis in both normal and tumor cells.[49] However, hypoxic conditions in tumor microenvironment especially, along with accumulation of genetic alternations often contribute to HIF-1 overexpression.[6]

Significant HIF-1 expression has been noted in most solid tumors studied, which include cancers of the colon, breast, pancreas, kidneys, prostate, ovary, brain, and bladder.[50][51] Clinically, elevated Hif-1a levels in a number of cancers, including cervical cancer, non-small-cell lung carcinoma, breast cancer (LV-positive and negative), oligodendroglioma, oropharyngeal cancer, ovarian cancer, endometrial cancer, esophageal cancer, head and neck cancer, and stomach cancer, have been associated with aggressive tumor progression, and thus has been implicated as a predictive and prognostic marker for resistance to radiation treatment, chemotherapy, and increased mortality.[19][52][53][54][55][56][57]

HIF1A expression may also regulate breast tumor progression. Elevated HIF1A levels may be detected in early cancer development, and have been found in early ductal carcinoma in situ, a pre-invasive stage in breast cancer development, and is also associated with increased microvasculature density in tumor lesions.[58] Moreover, despite histologically-determined low-grade, lymph-node negative breast tumor in a subset of patients examined, detection of significant HIF1A expression was able to independently predict poor response to therapy.[59] Similar findings have been reported in brain cancer and ovarian cancer studies as well, and suggest at regulatory role of HIF1A in initiating angiogenesis through interactions with pro-angiogenic factors such as VEGF.[60][61] Studies of glioblastoma multiforme show striking similarity between HIF1A expression pattern and that of VEGF gene transcription level.[62][63] In addition, high-grade glioblastoma multiform tumors with high VEGF expression pattern, similar to breast cancer with HIF1A overexpression, display significant signs of tumor neovascularization.[64] This further suggests the regulatory role of HIF1A in promoting tumor progression, likely through hypoxia-induced VEGF expression pathways.[65]

HIF1A overexpression in tumors may also occur in a hypoxia-independent pathway. In hemagioblastoma, HIF1A expression is found in most cells sampled from the well-vascularized tumor.[66] Although in both renal carcinoma and hemagioblastoma, the von Hippel-Lindau gene is inactivated, HIF1A is still expressed at high levels.[61][66][67] In addition to VEGF overexpression in response elevated HIF1A levels, the PI3K/AKT pathway is also involved in tumor growth. In prostate cancers, the commonly occurring PTEN mutation is associated with tumor progression toward aggressive stage, increased vascular density and angiogenesis.[68]

During hypoxia, tumor suppressor p53 overexpression may be associated with HIF1A-dependent pathway to initiate apoptosis. Moreover, p53-independent pathway may also induce apoptosis through the Bcl-2 pathway.[69] However, overexpression of HIF1A is cancer- and individual-specific, and depends on the accompanying genetic alternations and levels of pro- and anti-apoptotic factors present. One study on epithelial ovarian cancer shows HIF1A and nonfunctional tumor suppressor p53 is correlated with low levels of tumor cell apoptosis and poor prognosis.[70] Further, early-stage esophageal cancer patients with demonstrated overexpression of HIF1 and absence of BCL2 expression also failed photodynamic therapy.[71] Studies of glioblastoma multiforme show striking similarity between HIF1A protein expression pattern and that of VEGF gene transcription level.

While research efforts to develop therapeutic drugs to target hypoxia-associated tumor cells have been ongoing for many years, there has not yet been any breakthrough that has shown selectivity and effectiveness at targeting HIF1A pathways to decrease tumor progression and angiogenesis.[72] Successful therapeutic approaches in the future may also be highly case-specific to particular cancers ad individuals, and seem unlikely to be widely applicable due to the genetically heterogenous nature of the many cancer types and subtypes.

Interactions

HIF1A has been shown to interact with:

See also

References

  1. ↑ Semenza GL, Rue EA, Iyer NV, Pang MG, Kearns WG (June 1996). "Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q". Genomics. 34 (3): 437–9. doi:10.1006/geno.1996.0311. PMID 8786149.
  2. ↑ 2.0 2.1 Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (March 1997). "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway". J. Biol. Chem. 272 (13): 8581–93. doi:10.1074/jbc.272.13.8581. PMID 9079689.
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)".
  4. ↑ 4.0 4.1 Wang GL, Jiang BH, Rue EA, Semenza GL (Jun 1995). "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension". Proceedings of the National Academy of Sciences of the United States of America. 92 (12): 5510–5514. doi:10.1073/pnas.92.12.5510. PMC 41725. PMID 7539918.
  5. ↑ Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (Jan 1998). "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha". Genes & Development. 12 (2): 149–62. doi:10.1101/gad.12.2.149. PMC 316445. PMID 9436976.
  6. ↑ 6.0 6.1 6.2 Semenza GL (Oct 2003). "Targeting HIF-1 for cancer therapy". Nature Reviews. Cancer. 3 (10): 721–32. doi:10.1038/nrc1187. PMID 13130303.
  7. ↑ Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT, Sun YC, Huang HC, Yang YJ, Yang KD (March 2004). "Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts". J. Biol. Chem. 279 (11): 10331–7. doi:10.1074/jbc.M308013200. PMID 14681237.
  8. ↑ Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (Mar 1997). "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway". The Journal of Biological Chemistry. 272 (13): 8581–93. doi:10.1074/jbc.272.13.8581. PMID 9079689.
  9. ↑ Jiang BH, Zheng JZ, Leung SW, Roe R, Semenza GL (Aug 1997). "Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension". The Journal of Biological Chemistry. 272 (31): 19253–60. doi:10.1074/jbc.272.31.19253. PMID 9235919.
  10. ↑ Iyer NV, Leung SW, Semenza GL (Sep 1998). "The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation". Genomics. 52 (2): 159–65. doi:10.1006/geno.1998.5416. PMID 9782081.
  11. ↑ "Hypoxia-inducible factor 1-alpha". 2014.
  12. ↑ "HIF1A". National Center for Biotechnology Information.
  13. ↑ 13.0 13.1 Minet E, Ernest I, Michel G, Roland I, Remacle J, Raes M, Michiels C (Aug 1999). "HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5'UTR". Biochemical and Biophysical Research Communications. 261 (2): 534–40. doi:10.1006/bbrc.1999.0995. PMID 10425220.
  14. ↑ Danon A, Assouline G. "Antiulcer activity of hypertonic solutions in the rat: possible role of prostaglandins". European Journal of Pharmacology. 58 (4): 425–431. doi:10.1016/0014-2999(79)90313-3.
  15. ↑ Ladoux A, Frelin C (Nov 1997). "Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain transcription factors involved in adaptative responses to hypoxic stresses". Biochemical and Biophysical Research Communications. 240 (3): 552–556. doi:10.1006/bbrc.1997.7708. PMID 9398602.
  16. ↑ Wiener CM, Booth G, Semenza GL (Aug 1996). "In vivo expression of mRNAs encoding hypoxia-inducible factor 1". Biochemical and Biophysical Research Communications. 225 (2): 485–8. doi:10.1006/bbrc.1996.1199. PMID 8753788.
  17. ↑ Palmer LA, Semenza GL, Stoler MH, Johns RA (Feb 1998). "Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1". The American Journal of Physiology. 274 (2 Pt 1): L212-9. PMID 9486205.
  18. ↑ Wenger RH, Kvietikova I, Rolfs A, Gassmann M, Marti HH (Feb 1997). "Hypoxia-inducible factor-1 alpha is regulated at the post-mRNA level". Kidney International. 51 (2): 560–563. doi:10.1038/ki.1997.79. PMID 9027739.
  19. ↑ 19.0 19.1 Semenza GL (Oct 2003). "Targeting HIF-1 for cancer therapy". Nature Reviews. Cancer. 3 (10): 721–32. doi:10.1038/nrc1187. PMID 13130303.
  20. ↑ Bonello S, Zähringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, Görlach A (Apr 2007). "Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site". Arteriosclerosis, Thrombosis, and Vascular Biology. 27 (4): 755–761. doi:10.1161/01.ATV.0000258979.92828.bc. PMID 17272744.
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  26. ↑ Bruick RK, McKnight SL (Nov 2001). "A conserved family of prolyl-4-hydroxylases that modify HIF". Science. 294 (5545): 1337–40. doi:10.1126/science.1066373. PMID 11598268.
  27. ↑ 27.0 27.1 Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (Oct 2001). "C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation". Cell. 107 (1): 43–54. doi:10.1016/s0092-8674(01)00507-4. PMID 11595184.
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  29. ↑ Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (Apr 2001). "Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation". Science. 292 (5516): 468–72. doi:10.1126/science.1059796. PMID 11292861.
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  32. ↑ Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L (May 1997). "Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor". Proceedings of the National Academy of Sciences of the United States of America. 94 (11): 5667–72. doi:10.1073/pnas.94.11.5667. PMC 20836. PMID 9159130.
  33. ↑ Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ (Sep 2001). "Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation". The EMBO Journal. 20 (18): 5197–206. doi:10.1093/emboj/20.18.5197. PMC 125617. PMID 11566883.
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  39. ↑ Munkácsy, Gyöngyi; Sztupinszki, Zsófia; Herman, Péter; Bán, Bence; Pénzváltó, Zsófia; Szarvas, Nóra; Győrffy, Balázs (2016). "Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments". Molecular Therapy - Nucleic Acids. 5. doi:10.1038/mtna.2016.66. ISSN 2162-2531. PMC 5056990. PMID 28131298.
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  46. ↑ Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (Nov 1999). "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases". Cancer Research. 59 (22): 5830–5. PMID 10582706.
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  48. ↑ Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E (Mar 2003). "Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma". Cancer. 97 (6): 1573–81. doi:10.1002/cncr.11246. PMID 12627523.
  49. ↑ Vaupel P, Mayer A (Jun 2007). "Hypoxia in cancer: significance and impact on clinical outcome". Cancer Metastasis Reviews. 26 (2): 225–39. doi:10.1007/s10555-007-9055-1. PMID 17440684.
  50. ↑ Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (Aug 2000). "The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages". The American Journal of Pathology. 157 (2): 411–21. doi:10.1016/s0002-9440(10)64554-3. PMC 1850121. PMID 10934146.
  51. ↑ Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (Nov 1999). "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases". Cancer Research. 59 (22): 5830–5. PMID 10582706.
  52. ↑ Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL (Apr 2001). "Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer". Cancer Research. 61 (7): 2911–6. PMID 11306467.
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  54. ↑ Dvorák K (May 1990). "Intravenous systemic thrombolysis using streptokinase in the treatment of developing cardiogenic shock in myocardial infarct". Vnitr̆ní Lékar̆ství (in Czech). 36 (5): 426–34. PMID 2375073.
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  93. ↑ Yu F, White SB, Zhao Q, Lee FS (Aug 2001). "HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation". Proc. Natl. Acad. Sci. U.S.A. 98 (17): 9630–5. doi:10.1073/pnas.181341498. PMC 55503. PMID 11504942.
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Further reading

  • Semenza GL (2000). "HIF-1 and human disease: one highly involved factor". Genes Dev. 14 (16): 1983–91. PMID 10950862.
  • Semenza G (2002). "Signal transduction to hypoxia-inducible factor 1". Biochem. Pharmacol. 64 (5–6): 993–8. doi:10.1016/S0006-2952(02)01168-1. PMID 12213597.
  • Arbeit JM (2002). "Quiescent hypervascularity mediated by gain of HIF-1 alpha function". Cold Spring Harb. Symp. Quant. Biol. 67: 133–42. doi:10.1101/sqb.2002.67.133. PMID 12858534.
  • Sitkovsky M, Lukashev D (2005). "Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors". Nat. Rev. Immunol. 5 (9): 712–21. doi:10.1038/nri1685. PMID 16110315.
  • Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland JA (2005). "Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes". Histol. Histopathol. 20 (4): 1327–38. PMID 16136514.
  • Schipani E (2006). "Hypoxia and HIF-1 alpha in chondrogenesis". Semin. Cell Dev. Biol. 16 (4–5): 539–46. doi:10.1016/j.semcdb.2005.03.003. PMID 16144691.
  • Haase VH (2006). "Hypoxia-inducible factors in the kidney". Am. J. Physiol. Renal Physiol. 291 (2): F271–81. doi:10.1152/ajprenal.00071.2006. PMID 16554418.
  • Liang D, Kong X, Sang N (2006). "Effects of histone deacetylase inhibitors on HIF-1". Cell Cycle. 5 (21): 2430–5. doi:10.4161/cc.5.21.3409. PMID 17102633.
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