Array ( [0] => {{cs1 config|name-list-style=vanc}} [1] => {{Short description|Protein-coding gene in the species Homo sapiens}} [2] => {{Infobox_gene}} [3] => '''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]].{{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 | doi-access = free }}{{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 | pages = 8581–93 | date = March 1997 | pmid = 9079689 | doi = 10.1074/jbc.272.13.8581 | s2cid = 14908247 | doi-access = free }} [[The Nobel Prize|The Nobel Prize in Physiology or Medicine]] 2019 was awarded for the discovery of HIF. [4] => [5] => HIF1A 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]].{{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 = 5510–4 | date = June 1995 | pmid = 7539918 | pmc = 41725 | doi = 10.1073/pnas.92.12.5510 | bibcode = 1995PNAS...92.5510W | doi-access = free }}{{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 = January 1998 | pmid = 9436976 | pmc = 316445 | doi = 10.1101/gad.12.2.149 }} 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.{{cite journal | vauthors = Semenza GL | title = Targeting HIF-1 for cancer therapy | journal = Nature Reviews. Cancer | volume = 3 | issue = 10 | pages = 721–32 | date = October 2003 | pmid = 13130303 | doi = 10.1038/nrc1187 | s2cid = 2448376 }} The presence of HIF1A in a hypoxic environment is required to push forward normal placental development in early gestation. {{cite journal |last1=Soares |first1=Michael J. |title=Hypoxia and Placental Development |journal=Birth Defects Research |date=16 October 2017 |volume=109 |issue=17 |pages=4–6 |doi=10.1002/bdr2.1135 |pmid=29105383 |pmc=5743230 }} [6] => Two other [[alternative splicing|alternative transcripts]] encoding different [[isoforms]] have been identified.{{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 }} [7] => [8] => == Structure == [9] => [10] => HIF1 is a [[heterodimeric]] [[basic helix-loop-helix]] structure{{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 = The Journal of Biological Chemistry | volume = 279 | issue = 11 | pages = 10331–7 | date = March 2004 | pmid = 14681237 | doi = 10.1074/jbc.M308013200 | s2cid = 23881074 | doi-access = free }} 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. 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.{{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 | pages = 19253–60 | date = August 1997 | pmid = 9235919 | doi = 10.1074/jbc.272.31.19253 | s2cid = 19885003 | doi-access = free }} 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.{{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 | pages = 159–65 | date = September 1998 | pmid = 9782081 | doi = 10.1006/geno.1998.5416 | doi-access = free }}{{Cite web|url = https://www.uniprot.org/uniprot/Q16665|title = Hypoxia-inducible factor 1-alpha|date = 2014 }} [11] => [12] => == Gene and expression == [13] => [14] => The human ''HIF1A'' gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1).{{cite web | title = HIF1A | url = https://www.ncbi.nlm.nih.gov/gene/3091 | website = National Center for Biotechnology Information}} Its protein expression level can be measured by antibodies against HIF-1-alpha through various biological detection methods including western blot or immunostaining.{{Cite web|url=https://www.genetex.com/Product/Detail/HIF1-alpha-antibody/GTX127309|title=Anti-HIF1 alpha antibody (GTX127309) {{!}} GeneTex|website=www.genetex.com|access-date=2019-10-28}} ''HIF1A'' expression level is dependent on its GC-rich promoter activation.{{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 = August 1999 | pmid = 10425220 | doi = 10.1006/bbrc.1999.0995 }} 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.{{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 | pmid = 41725 | year=1979| doi-access = free }}{{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 = 552–6 | date = November 1997 | pmid = 9398602 | doi = 10.1006/bbrc.1997.7708 }}{{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 = August 1996 | pmid = 8753788 | doi = 10.1006/bbrc.1996.1199 | doi-access = free }}{{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 | pages = L212–9 | date = February 1998 | pmid = 9486205 | doi = 10.1152/ajplung.1998.274.2.L212 }}{{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 = 560–3 | date = February 1997 | pmid = 9027739 | doi = 10.1038/ki.1997.79 | doi-access = free }} Typically, oxygen-independent pathway regulates protein expression, and oxygen-dependent pathway regulates degradation. In hypoxia-independent ways, ''HIF1A'' expression may be upregulated through a [[redox]]-sensitive mechanism.{{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 = 755–61 | date = April 2007 | pmid = 17272744 | doi = 10.1161/01.ATV.0000258979.92828.bc | s2cid = 15292804 | doi-access = free }} [15] => [16] => == Function == [17] => [[File:HIF Nobel Prize Physiology Medicine 2019 Hegasy ENG.png|left|thumb|Nobel Prize in Physiology/ Medicine 2019: Cellular Oxygen Sensing and Adaption by Hif-alpha]] [18] => The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals.{{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 | url = http://rsp.ima-press.net/rsp/article/view/2307 }}{{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 = April 2000 | pmid = 10749844 | doi = 10.1152/jappl.2000.88.4.1474 | s2cid = 2395367 }} HIF1A activity is regulated by a host of [[post-translational modifications]]: [[hydroxylation]], [[acetylation]], and [[phosphorylation]]. 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.{{cite journal | vauthors = Semenza GL | title = HIF-1 and tumor progression: pathophysiology and therapeutics | journal = Trends in Molecular Medicine | volume = 8 | issue = 4 Suppl | pages = S62–7 | date = 2002 | pmid = 11927290 | doi = 10.1016/s1471-4914(02)02317-1 }}{{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 = February 2004 | pmid = 15031665 | doi = 10.1038/emm.2004.1 | s2cid = 41613739 | doi-access = free }} HIF-1 also induces transcription of genes involved in [[cell proliferation]] and survival, as well as glucose and iron [[metabolism]]. 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.{{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 = November 2001 | pmid = 11598268 | doi = 10.1126/science.1066373 | bibcode = 2001Sci...294.1337B | s2cid = 9695199 }}{{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 = October 2001 | pmid = 11595184 | doi = 10.1016/s0092-8674(01)00507-4 | s2cid = 18372306 | doi-access = free }}{{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 = April 2001 | pmid = 11292862 | doi = 10.1126/science.1059817 | bibcode = 2001Sci...292..464I | s2cid = 33725562 | doi-access = free }}{{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 = April 2001 | pmid = 11292861 | doi = 10.1126/science.1059796 | bibcode = 2001Sci...292..468J | s2cid = 20914281 | doi-access = free }}{{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 = September 2001 | pmid = 11566883 | pmc = 125617 | doi = 10.1093/emboj/20.18.5197 }} [19] => [20] => 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 {{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 = December 1996 | pmid = 8943284 | doi = 10.1074/jbc.271.50.32253 | s2cid = 11397503 | doi-access = free }}{{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 | pmc = 20836 | doi = 10.1073/pnas.94.11.5667 | bibcode = 1997PNAS...94.5667K | doi-access = free }} 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. 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.{{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 | doi-access = free | s2cid = 32080596 }} 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]].{{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 pVHL | journal = Nature | volume = 417 | issue = 6892 | pages = 975–8 | date = June 2002 | pmid = 12050673 | doi = 10.1038/nature00767 | s2cid = 4388644 }} Once the hydrolylated HIF1A is buried in the VHL protein, VHL will transport it to a proteasome to digest and destroy HIF1A. This prevents HIF1A from entering into the cell nucleus to carry out the transcription of many different regulatory pathways. Many of these pathways are necessary for proper placental development in early gestation. Under normoxic conditions the HIF1A will be hydroxylated and destroyed, which leads to placental tissue necrosis, disorganization, and overgrowth. {{cite journal |last1=Zhao |first1=Hui |last2=Wong |first2=Ronald J. |last3=Stevenson |first3=David K. |title=The Impact of Hypoxia in Early Pregnancy on Placental Cells |journal=International Journal of Molecular Sciences |date=7 September 2021 |volume=22 |issue=18 |pages=2–8 |doi=10.3390/ijms22189675 |doi-access=free |pmid=34575844 |pmc=8466283 }}{{cite journal |last1=Hung |first1=Tai-Ho |last2=Charnock-Jones |first2=D. Stephen |last3=Skepper |first3=Jeremy N. |last4=Burton |first4=Graham J. |title=Secretion of Tumor Necrosis Factor- from Human Placental Tissues Induced by Hypoxia-Reoxygenation Causes Endothelial Cell Activation in Vitro A Potential Mediator of the Inflammatory Response in Preeclampsia |journal=American Journal of Pathology |date=3 March 2004 |volume=164 |issue=3 |pages=1049–1061 |doi=10.1016/S0002-9440(10)63192-6 |pmid=14982858 |pmc=1614718 |url=https://ajp.amjpathol.org/article/S0002-9440(10)63192-6/fulltext }}The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia.{{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 | pmc = 133771 | doi = 10.1128/mcb.22.9.2984-2992.2002 }} Function of HIF1A gene can be effectively examined by siRNA knockdown based on an independent validation.{{cite journal | vauthors = Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, Győrffy B | title = Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments | language = en | journal = Molecular Therapy: Nucleic Acids | volume = 5 | issue = 9 | pages = e366 | date = September 2016 | pmid = 27673562 | pmc = 5056990 | doi = 10.1038/mtna.2016.66 }} [21] => [22] => === Repair, regeneration and rejuvenation === [23] => [24] => In normal circumstances after injury HIF1A 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.{{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 | access-date = 3 July 2015 }}{{cite journal | vauthors = Zhang Y, Strehin I, Bedelbaeva K, Gourevitch D, Clark L, Leferovich J, Messersmith PB, Heber-Katz E | display-authors = 6 | title = Drug-induced regeneration in adult mice | journal = Science Translational Medicine | volume = 7 | issue = 290 | pages = 290ra92 | date = June 2015 | pmid = 26041709 | pmc = 4687906 | doi = 10.1126/scitranslmed.3010228 }} One such regenerative process in which HIF1A is involved is [[Nerve injury|peripheral nerve regeneration]]. Following axon injury, HIF1A activates [[Vascular endothelial growth factor A|VEGFA]] to promote regeneration and functional recovery.{{cite journal | vauthors = Cho Y, Shin JE, Ewan EE, Oh YM, Pita-Thomas W, Cavalli V | title = Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α | journal = Neuron | volume = 88 | issue = 4 | pages = 720–34 | date = November 2015 | pmid = 26526390 | pmc = 4655162 | doi = 10.1016/j.neuron.2015.09.050 }}{{cite journal | vauthors = Mahar M, Cavalli V | title = Intrinsic mechanisms of neuronal axon regeneration | language = En | journal = Nature Reviews. Neuroscience | volume = 19 | issue = 6 | pages = 323–337 | date = June 2018 | pmid = 29666508 | pmc = 5987780 | doi = 10.1038/s41583-018-0001-8 }} HIF1A also controls skin healing.{{cite journal | vauthors = Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, Paik KJ, Duscher D, Gurtner GC, Lorenz HP, Longaker MT | display-authors = 6 | title = The Role of Hypoxia-Inducible Factor in Wound Healing | journal = Advances in Wound Care | volume = 3 | issue = 5 | pages = 390–399 | date = May 2014 | pmid = 24804159 | pmc = 4005494 | doi = 10.1089/wound.2013.0520 }} Researchers at the [[Stanford University School of Medicine]] demonstrated that HIF1A activation was able to prevent and treat chronic wounds in diabetic and aged mice. Not only did the wounds in the mice heal more quickly, but the quality of the new skin was even better than the original.{{Cite web|date=2015-01-23|title=Skin patch could help heal, prevent diabetic ulcers, study finds|url=https://biox.stanford.edu/highlight/skin-patch-could-help-heal-prevent-diabetic-ulcers-study-finds|access-date=2020-12-04|website=Welcome to Bio-X|publisher=© Stanford University, Stanford, California 94305|language=en}}{{cite journal | vauthors = Duscher D, Neofytou E, Wong VW, Maan ZN, Rennert RC, Inayathullah M, Januszyk M, Rodrigues M, Malkovskiy AV, Whitmore AJ, Walmsley GG, Galvez MG, Whittam AJ, Brownlee M, Rajadas J, Gurtner GC | display-authors = 6 | title = Transdermal deferoxamine prevents pressure-induced diabetic ulcers | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 1 | pages = 94–9 | date = January 2015 | pmid = 25535360 | pmc = 4291638 | doi = 10.1073/pnas.1413445112 | bibcode = 2015PNAS..112...94D | doi-access = free }}{{cite journal | vauthors = Duscher D, Trotsyuk AA, Maan ZN, Kwon SH, Rodrigues M, Engel K, Stern-Buchbinder ZA, Bonham CA, Barrera J, Whittam AJ, Hu MS, Inayathullah M, Rajadas J, Gurtner GC | display-authors = 6 | title = Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds | journal = Journal of Controlled Release | volume = 308 | pages = 232–239 | date = August 2019 | pmid = 31299261 | doi = 10.1016/j.jconrel.2019.07.009 | s2cid = 196350143 | url = https://pubmed.ncbi.nlm.nih.gov/31299261/ }}{{cite journal | vauthors = Bonham CA, Rodrigues M, Galvez M, Trotsyuk A, Stern-Buchbinder Z, Inayathullah M, Rajadas J, Gurtner GC | display-authors = 6 | title = Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice | journal = Wound Repair and Regeneration | volume = 26 | issue = 3 | pages = 300–305 | date = May 2018 | pmid = 30152571 | pmc = 6238634 | doi = 10.1111/wrr.12667 }} Additionally the regenerative effect of HIF-1A modulation on aged skin cells was described{{cite journal | vauthors = Pagani A, Aitzetmüller MM, Brett EA, König V, Wenny R, Thor D, Radtke C, Huemer GM, Machens HG, Duscher D | display-authors = 6 | title = Skin Rejuvenation through HIF-1α Modulation | journal = Plastic and Reconstructive Surgery | volume = 141 | issue = 4 | pages = 600e–607e | date = April 2018 | pmid = 29596193 | doi = 10.1097/PRS.0000000000004256 | s2cid = 4473259 | url = https://pubmed.ncbi.nlm.nih.gov/29596193/ }}{{cite journal | vauthors = Pagani A, Kirsch BM, Hopfner U, Aitzetmueller MM, Brett EA, Thor D, Mela P, Machens HG, Duscher D | display-authors = 6 | title = Deferiprone Stimulates Aged Dermal Fibroblasts Via HIF-1α Modulation | journal = Aesthetic Surgery Journal | date = June 2020 | volume = 41 | issue = 4 | pages = 514–524 | pmid = 32479616 | doi = 10.1093/asj/sjaa142|issn=1090-820X | url = https://pubmed.ncbi.nlm.nih.gov/32479616/ }} and a rejuvenating effect on aged facial skin was demonstrated in patients.{{cite journal | vauthors = Duscher D, Maan ZN, Hu MS, Thor D | title = A single-center blinded randomized clinical trial to evaluate the anti-aging effects of a novel HSF™-based skin care formulation | journal = Journal of Cosmetic Dermatology | volume = 19 | issue = 11 | pages = 2936–2945 | date = November 2020 | pmid = 32306525 | doi = 10.1111/jocd.13356 | s2cid = 216031505 | doi-access = free }} HIF modulation has also been linked to a beneficial effect on hair loss.{{cite journal | vauthors = Houschyar KS, Borrelli MR, Tapking C, Popp D, Puladi B, Ooms M, Chelliah MP, Rein S, Pförringer D, Thor D, Reumuth G, Wallner C, Branski LK, Siemers F, Grieb G, Lehnhardt M, Yazdi AS, Maan ZN, Duscher D | display-authors = 6 | title = Molecular Mechanisms of Hair Growth and Regeneration: Current Understanding and Novel Paradigms | journal = Dermatology | volume = 236 | issue = 4 | pages = 271–280 | date = 2020 | pmid = 32163945 | doi = 10.1159/000506155 | s2cid = 212693280 | doi-access = free }} The biotech company Tomorrowlabs GmbH, founded in Vienna in 2016 by the physician [[Dominik Duscher]] and pharmacologist [[Dominik Thor]], makes use of this mechanism.{{Cite web|last=Tomorrowlabs|title=Tomorrowlabs|url=https://www.tomorrowlabs.at/|access-date=2020-12-04|website=Tomorrowlabs|language=en}} Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.{{Cite web|title=Kosmetikbranche: Wie das Beauty-Start-up Tomorrowlabs den Markt erobert|url=https://www.handelsblatt.com/unternehmen/mittelstand/familienunternehmer/kosmetikbranche-wie-das-beauty-start-up-tomorrowlabs-den-markt-erobert/25523424.html|access-date=2020-12-04|website=www.handelsblatt.com|language=de}}{{Cite web|title=Ein Protein gegen das Altern und für das Geldverdienen|url=https://www.nachrichten.at/wirtschaft/wirtschaftsraumooe/ein-protein-gegen-das-altern-und-fuer-das-geldverdienen;art467,3277897|access-date=2020-12-04|website=nachrichten.at|language=de}}{{Cite web|title=Das neue Beauty-Investment von Michael Pieper - HZ|url=https://www.handelszeitung.ch/unternehmen/das-neue-beauty-investment-von-michael-pieper|access-date=2020-12-04|website=Handelszeitung|language=de}}{{Cite web|last=andrea.hodoschek|date=2020-08-03|title=Milliardenmarkt Anti-Aging: Start-up aus Österreich mischt mit|url=https://kurier.at/wirtschaft/wirtschaft-von-innen/milliardenmarkt-anti-aging-start-up-aus-oesterreich-mischt-mit/400989071|access-date=2020-12-04|website=kurier.at|language=de}} [25] => [26] => == Regulation == [27] => [28] => HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an [[NF-κB]]-dependent manner.{{cite journal | vauthors = van Uden P, Kenneth NS, Rocha S | title = Regulation of hypoxia-inducible factor-1alpha by NF-kappaB | journal = The Biochemical Journal | volume = 412 | issue = 3 | pages = 477–84 | date = June 2008 | pmid = 18393939 | pmc = 2474706 | doi = 10.1042/BJ20080476 | url = http://www.hif1.com }}Rius, J., Guma, M., Schachtrup, C. ''et al.'' [https://www.nature.com/articles/nature06905 NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α.] ''Nature'' 453, 807–811 (2008). https://doi.org/10.1038/nature06905 In addition, the coordinated activity of the [[prolyl hydroxylase]]s (PHDs) maintain the appropriate balance of HIF1A protein in the post-translation phase.{{cite journal | vauthors = Semenza GL | title = Hydroxylation of HIF-1: oxygen sensing at the molecular level | journal = Physiology | volume = 19 | issue = 4 | pages = 176–82 | date = August 2004 | pmid = 15304631 | doi = 10.1152/physiol.00001.2004 | s2cid = 2434206 }} [29] => [30] => PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as [[desferrioxamine]] (DFO) have proven successful in HIF1A stabilization.{{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 = International Journal of Medical Sciences | volume = 10 | issue = 10 | pages = 1412–21 | year = 2013 | pmid = 23983604 | pmc = 3752727 | doi = 10.7150/ijms.5630 }} HBO ([[Hyperbaric medicine|Hyperbaric oxygen therapy]]) and HIF1A imitators such as cobalt chloride have also been successfully utilized. [31] => [32] => Factors increasing HIF1A{{cite journal | vauthors = Yee Koh M, Spivak-Kroizman TR, Powis G | title = HIF-1 regulation: not so easy come, easy go | journal = Trends in Biochemical Sciences | volume = 33 | issue = 11 | pages = 526–34 | date = November 2008 | pmid = 18809331 | doi = 10.1016/j.tibs.2008.08.002 }} [33] => {{div col|colwidth=20em}} [34] => [35] => * Modulator of Degradation: [36] => ** Oxygen-Dependent: [37] => *** [[UBE2S|EPF UCP]] (degrades pHVL) [38] => *** [[USP20|VDU2]] (de-ubiquitinates HIF1A) [39] => *** [[SUMO protein|SUMOylation]] (via [[RWDD3|RSUME]]) [40] => *** DeSUMOylation ( via [[SENP1]]) [41] => ** Oxygen-independent: [42] => *** [[Calcineurin|Calcineurin A]] ( Ca2+-dependent via [[GNB2L1|RACK1]]) [43] => * Modulators of translation: [44] => ** RNA-binding proteins, [[PTBP1|PTB]], and [[ELAVL1|HuR]] [45] => ** [[PtdIns3K]] and [[MAPK/ERK pathway|MAPK]] pathways [46] => ** [[Internal ribosome entry site|IRES]]-mediated translation [47] => ** calcium signaling [48] => ** [[miRNA]]s [49] => {{Div col end}} [50] => [51] => Factors decreasing HIF1A [52] => {{div col|colwidth=20em}} [53] => * Modulator of Degradation: [54] => ** Oxygen-Dependent: [55] => *** [[Prolyl hydroxylase|PHD]], [[Von Hippel–Lindau tumor suppressor|VHL]], [[OS-9]] and [[SAT2|SSAT2]] [56] => *** SUMOylation [57] => ** Oxygen-independent [58] => *** [[RACK1]] and [[SAT1 (gene)|SSAT1]] [59] => *** [[GSK3B|GSK3β]] [60] => *** [[FOXO4]] [61] => *Modulators of translation: [62] => ** Calcium signaling [63] => ** miRNAs [64] => {{Div col end}} [65] => [66] => == Role in cancer == [67] => [68] => HIF1A is overexpressed in many human cancers.{{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 | pages = 5830–5 | date = November 1999 | pmid = 10582706 }}{{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 | pages = 411–21 | date = August 2000 | pmid = 10934146 | pmc = 1850121 | doi = 10.1016/s0002-9440(10)64554-3 }} HIF1A overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia.{{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 | pages = 1573–81 | date = March 2003 | pmid = 12627523 | doi = 10.1002/cncr.11246 | s2cid = 32635739 | doi-access = free }} Hypoxia promotes apoptosis in both normal and tumor cells.{{cite journal | vauthors = Vaupel P, Mayer A | title = Hypoxia in cancer: significance and impact on clinical outcome | journal = Cancer and Metastasis Reviews | volume = 26 | issue = 2 | pages = 225–39 | date = June 2007 | pmid = 17440684 | doi = 10.1007/s10555-007-9055-1 | s2cid = 21902400 }} However, hypoxic conditions in [[tumor microenvironment]] especially, along with accumulation of genetic alternations often contribute to ''HIF1A '' overexpression. [69] => [70] => Significant HIF1A expression has been noted in most solid tumors studied, which include cancers of the [[gastric]], [[Large intestine|colon]], [[breast]], [[pancreas]], [[kidneys]], [[prostate]], [[ovary]], [[brain]], and [[bladder]].{{cite journal | vauthors = Ezzeddini R, Taghikhani M, Somi MH, Samadi N, Rasaee, MJ | title = Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma | journal = Life Sciences | volume = 224 | pages = 169–176 | date = May 2019 | pmid = 30914315 | doi = 10.1016/j.lfs.2019.03.056 | s2cid = 85532042 | url = https://www.sciencedirect.com/science/article/abs/pii/S0024320519302206 }} Clinically, elevated HIF1A 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.{{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 | pages = 2911–6 | date = April 2001 | pmid = 11306467 }}{{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 | pages = 266–76 | date = February 2001 | pmid = 11181773 | doi = 10.1093/jnci/93.4.266 | doi-access = free }}{{cite journal | vauthors = Dvorák K | title = [Intravenous systemic thrombolysis using streptokinase in the treatment of developing cardiogenic shock in myocardial infarct] | language = cs | journal = Vnitrni Lekarstvi | volume = 36 | issue = 5 | pages = 426–34 | date = May 1990 | pmid = 2375073 }}{{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 = June 2001 | pmid = 11410504 }}{{cite journal | vauthors = Ezzeddini R, Taghikhani M, Salek Farrokhi A, Somi MH, Samadi N, Esfahani A, Rasaee, MJ | title = Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance | journal = Journal of Physiology and Biochemistry | volume = 77 | issue = 2 | pages = 249–260 | date = May 2021 | pmid = 33730333 | doi = 10.1007/s13105-021-00791-3 | s2cid = 232300877 | url = https://pubmed.ncbi.nlm.nih.gov/33730333/| issn = }} 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]].{{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 = February 2001 | pmid = 11181778 | doi = 10.1093/jnci/93.4.309 | doi-access = free }} 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. 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]].{{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 | pages = 2606–18 | date = June 2000 | pmid = 10861440 | doi = 10.1002/1097-0142(20000601)88:11<2606::aid-cncr25>3.0.co;2-w | s2cid = 85168033 | doi-access = free }} [71] => Studies of [[glioblastoma multiforme]] show striking similarity between HIF1A expression pattern and that of [[VEGF]] [[gene transcription]] level.{{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 | pages = 339–56, ix | date = April 2001 | pmid = 11382591 | doi = 10.1016/S1055-3207(18)30069-3}}{{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 | pages = 647–54 | date = May 2004 | doi = 10.1158/1535-7163.647.3.5 | pmid = 15141023 | doi-access = free }} 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]].{{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 | pages = 109–17 | date = February 1997 | pmid = 9039457 | doi = 10.1007/s004010050591 | s2cid = 20164007 }} This further suggests the regulatory role of HIF1A in promoting tumor progression, likely through hypoxia-induced VEGF expression pathways. [72] => [73] => [74] => HIF1A overexpression in tumors may also occur in a hypoxia-independent pathway. In hemangioblastoma, HIF1A expression is found in most cells sampled from the well-vascularized tumor.{{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 | pages = 5435–43 | date = November 2000 | pmid = 11114720 | doi = 10.1038/sj.onc.1203938 | s2cid = 28480163 }} Although in both renal carcinoma and hemangioblastoma, the von Hippel-Lindau gene is inactivated, HIF1A is still expressed at high levels. 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.{{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 | pages = 391–6 | date = February 2000 | doi = 10.1101/gad.14.4.391 | pmid = 10691731 | pmc = 316386 }} [75] => [76] => 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. 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. Further, early-stage esophageal cancer patients with demonstrated overexpression of HIF1 and absence of BCL2 expression also failed photodynamic therapy.{{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 = March 2001 | pmid = 11280732 }} [77] => [78] => 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.{{cite journal | vauthors = Liu XW, Cai TY, Zhu H, Cao J, Su Y, Hu YZ, He QJ, Yang B | title = Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma | journal = Autophagy | volume = 10 | issue = 1 | pages = 111–22 | date = January 2014 | pmid = 24220190 | pmc = 4389865 | doi = 10.4161/auto.26838 }} Successful therapeutic approaches in the future may also be highly case-specific to particular cancers and individuals, and seem unlikely to be widely applicable due to the genetically [[heterogenous]] nature of the many cancer types and subtypes. [79] => [80] => == Interactions == [81] => [82] => HIF1A has been shown to [[Protein-protein interaction|interact]] with: [83] => {{div col|colwidth=20em}} [84] => * [[ARNTL]],{{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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 10 | pages = 5474–9 | date = May 1998 | pmid = 9576906 | pmc = 20401 | doi = 10.1073/pnas.95.10.5474 | bibcode = 1998PNAS...95.5474H | doi-access = free }} [85] => * [[Aryl hydrocarbon receptor nuclear translocator|ARNT]],{{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 = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10236–43 | date = March 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 | s2cid = 25125998 | doi-access = free }} [86] => * [[CREB binding protein|CREBB]],{{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 = The EMBO Journal | volume = 18 | issue = 7 | pages = 1905–14 | date = April 1999 | pmid = 10202154 | pmc = 1171276 | doi = 10.1093/emboj/18.7.1905 }}{{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 & Development | volume = 13 | issue = 1 | pages = 64–75 | date = January 1999 | pmid = 9887100 | pmc = 316375 | doi = 10.1101/gad.13.1.64 }}{{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 = Molecular Pharmacology | volume = 74 | issue = 1 | pages = 236–45 | date = July 2008 | pmid = 18426857 | doi = 10.1124/mol.108.045278 | s2cid = 31675735 }} [87] => * [[EP300]],{{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 = February 2002 | pmid = 11823643 | doi = 10.1126/science.1068592 | bibcode = 2002Sci...295..858L | s2cid = 24045310 }}{{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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 8 | pages = 5367–72 | date = April 2002 | pmid = 11959990 | pmc = 122775 | doi = 10.1073/pnas.082117899 | bibcode = 2002PNAS...99.5367F | doi-access = free }} [88] => * [[HIF1AN]],{{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 & Development | volume = 15 | issue = 20 | pages = 2675–86 | date = October 2001 | pmid = 11641274 | pmc = 312814 | doi = 10.1101/gad.924501 }} [89] => * [[Mdm2]], [90] => * [[Nerve Growth factor IB|NR4A]],{{cite journal | vauthors = Kim BY, Kim H, Cho EJ, Youn HD | title = Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation | journal = Experimental & Molecular Medicine | volume = 40 | issue = 1 | pages = 71–83 | date = February 2008 | pmid = 18305400 | pmc = 2679322 | doi = 10.3858/emm.2008.40.1.71 }} [91] => * [[P53]],{{cite journal | vauthors = Chen D, Li M, Luo J, Gu W | title = Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function | journal = The Journal of Biological Chemistry | volume = 278 | issue = 16 | pages = 13595–8 | date = April 2003 | pmid = 12606552 | doi = 10.1074/jbc.C200694200 | s2cid = 85351036 | doi-access = free }}{{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 & Development | volume = 14 | issue = 1 | pages = 34–44 | date = January 2000 | pmid = 10640274 | pmc = 316350 | doi = 10.1101/gad.14.1.34 }}{{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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 16 | pages = 10305–9 | date = August 2002 | pmid = 12124396 | pmc = 124909 | doi = 10.1073/pnas.122347199 | bibcode = 2002PNAS...9910305H | doi-access = free }}{{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 = March 1998 | pmid = 9537326 | doi = 10.1038/32925 | bibcode = 1998Natur.392..405A | s2cid = 4423081 }} [92] => * [[PSMA7]],{{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 Letters | volume = 498 | issue = 1 | pages = 62–6 | date = June 2001 | pmid = 11389899 | doi = 10.1016/S0014-5793(01)02499-1 | s2cid = 83756271 }} [93] => * [[STAT3]],{{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 = Experimental & Molecular Medicine | volume = 40 | issue = 5 | pages = 479–85 | date = October 2008 | pmid = 18985005 | pmc = 2679355 | doi = 10.3858/emm.2008.40.5.479 }} [94] => * [[Ubiquitin C|UBC]], [95] => * [[Von Hippel-Lindau tumor suppressor|VH]]{{cite journal | vauthors = André H, Pereira TS | title = Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha | journal = The Journal of Biological Chemistry | volume = 283 | issue = 43 | pages = 29375–84 | date = October 2008 | pmid = 18694926 | pmc = 2662024 | doi = 10.1074/jbc.M805919200 | doi-access = free }}{{cite journal | vauthors = Corn PG, McDonald ER, Herman JG, El-Deiry WS|author-link3=James G. Herman | 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 = Nature Genetics | volume = 35 | issue = 3 | pages = 229–37 | date = November 2003 | pmid = 14556007 | doi = 10.1038/ng1254 |s2cid=22798700 }}{{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 = The EMBO Journal | volume = 22 | issue = 8 | pages = 1857–67 | date = April 2003 | pmid = 12682018 | pmc = 154465 | doi = 10.1093/emboj/cdg173 }}{{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 = The EMBO Journal | volume = 19 | issue = 16 | pages = 4298–309 | date = August 2000 | pmid = 10944113 | pmc = 302039 | doi = 10.1093/emboj/19.16.4298 }}{{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 = June 2002 | pmid = 12004076 | doi = 10.1126/science.1073440 | bibcode = 2002Sci...296.1886M | s2cid = 19641938 | doi-access = free }}{{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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 17 | pages = 9630–5 | date = August 2001 | pmid = 11504942 | pmc = 55503 | doi = 10.1073/pnas.181341498 | bibcode = 2001PNAS...98.9630Y | doi-access = free }} and [96] => * [[Von Hippel–Lindau tumor suppressor|VHL]].{{cite journal | vauthors = Haase VH | title = The VHL tumor suppressor: master regulator of HIF | journal = Current Pharmaceutical Design | volume = 15 | issue = 33 | pages = 3895–903 | year = 2009 | pmid = 19671042 | pmc = 3622710 | doi = 10.2174/138161209789649394 }} [97] => * [[Glucocorticoid receptor|GR (NR3C1)]].{{cite journal | vauthors = Sun YY, Wang CY, Hsu MF, Juan SH, Chang CY, Chou CM, Yang LY, Hung KS, Xu J, Lee YH, Hsu CY | title = Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1alpha in a cell-type-specific manner | journal = The Journal of Neuroscience | volume = 30 | issue = 28 | pages = 9621–30 | date = July 2010 | pmid = 20631191 | pmc = 6632428 | doi = 10.1523/JNEUROSCI.2295-10.2010 }}{{cite journal | vauthors = Menshanov PN, Bannova AV, Dygalo NN | title = Anoxia ameliorates the dexamethasone-induced neurobehavioral alterations in the neonatal male rat pups | journal = Hormones and Behavior | volume = 87 | pages = 122–128 | date = January 2017 | pmid = 27865789 | doi = 10.1016/j.yhbeh.2016.11.013 | s2cid = 4108143 }} [98] => {{Div col end}} [99] => [100] => == See also == [101] => * [[Hypoxia inducible factors]] [102] => [103] => == References == [104] => {{Reflist|colwidth=33em}} [105] => [106] => == Further reading == [107] => {{refbegin|colwidth=33em}} [108] => * {{cite journal | vauthors = Semenza GL | title = HIF-1 and human disease: one highly involved factor | journal = Genes & Development | volume = 14 | issue = 16 | pages = 1983–91 | date = August 2000 | doi = 10.1101/gad.14.16.1983 | pmid = 10950862 | s2cid = 12788170 | doi-access = free }} [109] => * {{cite journal | vauthors = Semenza G | title = Signal transduction to hypoxia-inducible factor 1 | journal = Biochemical Pharmacology | volume = 64 | issue = 5–6 | pages = 993–8 | date = September 2002 | pmid = 12213597 | doi = 10.1016/S0006-2952(02)01168-1 }} [110] => * {{cite journal | vauthors = Arbeit JM | title = Quiescent hypervascularity mediated by gain of HIF-1 alpha function | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 67 | pages = 133–42 | year = 2002 | pmid = 12858534 | doi = 10.1101/sqb.2002.67.133 }} [111] => * {{cite journal | vauthors = Sitkovsky M, Lukashev D | title = Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors | journal = Nature Reviews. Immunology | volume = 5 | issue = 9 | pages = 712–21 | date = September 2005 | pmid = 16110315 | doi = 10.1038/nri1685 | s2cid = 30400163 }} [112] => * {{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 = Histology and Histopathology | volume = 20 | issue = 4 | pages = 1327–38 | date = October 2005 | pmid = 16136514 | doi = 10.14670/HH-20.1327 }} [113] => * {{cite journal | vauthors = Schipani E | title = Hypoxia and HIF-1 alpha in chondrogenesis | journal = Seminars in Cell & Developmental Biology | volume = 16 | issue = 4–5 | pages = 539–46 | year = 2006 | pmid = 16144691 | doi = 10.1016/j.semcdb.2005.03.003 }} [114] => * {{cite journal | vauthors = Haase VH | title = Hypoxia-inducible factors in the kidney | journal = American Journal of Physiology. Renal Physiology | volume = 291 | issue = 2 | pages = F271–81 | date = August 2006 | pmid = 16554418 | pmc = 4232221 | doi = 10.1152/ajprenal.00071.2006 }} [115] => * {{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 | date = November 2006 | pmid = 17102633 | pmc = 4505804 | doi = 10.4161/cc.5.21.3409 }} [116] => {{refend}} [117] => [118] => == External links == [119] => * {{PDBe-KB2|Q16665|Human Hypoxia-inducible factor 1-alpha}} [120] => * {{PDBe-KB2|Q61221|Mouse Hypoxia-inducible factor 1-alpha}} [121] => * Scientific animation of HIF-1alpha in complex with ARNT on DNA: https://www.youtube.com/watch?v=azIEzLXXyHM [122] => [123] => {{PDB Gallery|geneid=3091}} [124] => {{Transcription factors|g1}} [125] => [126] => {{DEFAULTSORT:Hif1a}} [127] => [[Category:Transcription factors]] [128] => [[Category:PAS-domain-containing proteins]] [] => )
good wiki

HIF1A

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. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.

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