Biology:HIF1A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

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.[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][2] 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.[8] 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.[9][10]

Gene and expression

The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1).[11] Its protein expression level can be measured by antibodies against HIF-1-alpha through various biological detection methods including western blot or immunostaining.[12] HIF1A expression level is dependent 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.[6] In hypoxia-independent ways, HIF1A expression may be upregulated through a redox-sensitive mechanism.[19]

Function

Nobel Prize in Physiology/ Medicine 2019: Cellular Oxygen Sensing and Adaption by Hif-alpha

The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals.[20][21] HIF1A activity is regulated by a host of post-translational modifications: hydroxylation, acetylation, and phosphorylation.[22] 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][23][22] HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism.[22] 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.[24][25][26][27][28]

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 [29][30] 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.[28] 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.[25][31] 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.[32][33] The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia.[34][35] Function of HIF1A gene can be effectively examined by siRNA knockdown based on an independent validation.[36]

Repair, regeneration and rejuvenation

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.[37][38] One such regenerative process in which HIF1A is involved is peripheral nerve regeneration. Following axon injury, HIF1A activates VEGFA to promote regeneration and functional recovery.[39][40] HIF1A also controls skin healing.[41] 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.[42][43][44][45] Additionally the regenerative effect of HIF-1A modulation on aged skin cells was described[46][47] and a rejuvenating effect on aged facial skin was demonstrated in patients.[48] HIF modulation has also been linked to a beneficial effect on hair loss.[49] The biotech company Tomorrowlabs GmbH, founded in Vienna in 2016 by the physician Dominik Duscher and pharmacologist Dominik Thor, makes use of this mechanism.[50] Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.[51][52][53][54]

Regulation

HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an NF-κB-dependent manner.[55][56] In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF1A protein in the post-translation phase.[57]

PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as desferrioxamine (DFO) have proven successful in HIF1A stabilization.[58] HBO (Hyperbaric oxygen therapy) and HIF1A imitators such as cobalt chloride have also been successfully utilized.[58]

Factors increasing HIF1A[59]


  • Modulator of Degradation:
    • Oxygen-Dependent:
      • EPF UCP (degrades pHVL)
      • VDU2 (de-ubiquitinates HIF1A)
      • SUMOylation (via RSUME)
      • DeSUMOylation ( via SENP1)
    • Oxygen-independent:
  • Modulators of translation:
    • RNA-binding proteins, PTB, and HuR
    • PtdIns3K and MAPK pathways
    • IRES-mediated translation
    • calcium signaling
    • miRNAs


Factors decreasing HIF1A[59]

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


Role in cancer

HIF1A is overexpressed in many human cancers.[60][61] HIF1A overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia.[62] Hypoxia promotes apoptosis in both normal and tumor cells.[63] However, hypoxic conditions in tumor microenvironment especially, along with accumulation of genetic alternations often contribute to HIF1A overexpression.[6]

Significant HIF1A expression has been noted in most solid tumors studied, which include cancers of the gastric, colon, breast, pancreas, kidneys, prostate, ovary, brain, and bladder.[64][61][60] 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.[6][65][66][67][68][64][69] 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.[70] 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.[62] 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.[68][71] Studies of glioblastoma multiforme show striking similarity between HIF1A expression pattern and that of VEGF gene transcription level.[72][73] 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.[74] This further suggests the regulatory role of HIF1A in promoting tumor progression, likely through hypoxia-induced VEGF expression pathways.[73]

[64] 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.[75] Although in both renal carcinoma and hemangioblastoma, the von Hippel-Lindau gene is inactivated, HIF1A is still expressed at high levels.[71][75][60] 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.[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.[63] 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.[68] Further, early-stage esophageal cancer patients with demonstrated overexpression of HIF1 and absence of BCL2 expression also failed photodynamic therapy.[77]

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.[78] 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.

Interactions

HIF1A has been shown to interact with:


See also

  • Hypoxia inducible factors

References

  1. ↑ "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. June 1996. doi:10.1006/geno.1996.0311. PMID 8786149. 
  2. ↑ 2.0 2.1 2.2 "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. March 1997. 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)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3091. 
  4. ↑ 4.0 4.1 "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): 5510–4. June 1995. doi:10.1073/pnas.92.12.5510. PMID 7539918. Bibcode: 1995PNAS...92.5510W. 
  5. ↑ "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha". Genes & Development 12 (2): 149–62. January 1998. doi:10.1101/gad.12.2.149. PMID 9436976. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Targeting HIF-1 for cancer therapy". Nature Reviews. Cancer 3 (10): 721–32. October 2003. doi:10.1038/nrc1187. PMID 13130303. 
  7. ↑ "Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts". The Journal of Biological Chemistry 279 (11): 10331–7. March 2004. doi:10.1074/jbc.M308013200. PMID 14681237. 
  8. ↑ "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. August 1997. doi:10.1074/jbc.272.31.19253. PMID 9235919. 
  9. ↑ "The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation". Genomics 52 (2): 159–65. September 1998. doi:10.1006/geno.1998.5416. PMID 9782081. 
  10. ↑ "Hypoxia-inducible factor 1-alpha". 2014. https://www.uniprot.org/uniprot/Q16665. 
  11. ↑ "HIF1A". https://www.ncbi.nlm.nih.gov/gene/3091. 
  12. ↑ "Anti-HIF1 alpha antibody (GTX127309) | GeneTex". https://www.genetex.com/Product/Detail/HIF1-alpha-antibody/GTX127309. 
  13. ↑ 13.0 13.1 "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. August 1999. doi:10.1006/bbrc.1999.0995. PMID 10425220. 
  14. ↑ "Antiulcer activity of hypertonic solutions in the rat: possible role of prostaglandins". European Journal of Pharmacology 58 (4): 425–431. 1979. doi:10.1016/0014-2999(79)90313-3. PMID 41725. 
  15. ↑ "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): 552–6. November 1997. doi:10.1006/bbrc.1997.7708. PMID 9398602. 
  16. ↑ "In vivo expression of mRNAs encoding hypoxia-inducible factor 1". Biochemical and Biophysical Research Communications 225 (2): 485–8. August 1996. doi:10.1006/bbrc.1996.1199. PMID 8753788. 
  17. ↑ "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. February 1998. doi:10.1152/ajplung.1998.274.2.L212. PMID 9486205. 
  18. ↑ "Hypoxia-inducible factor-1 alpha is regulated at the post-mRNA level". Kidney International 51 (2): 560–3. February 1997. doi:10.1038/ki.1997.79. PMID 9027739. 
  19. ↑ "Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site". Arteriosclerosis, Thrombosis, and Vascular Biology 27 (4): 755–61. April 2007. doi:10.1161/01.ATV.0000258979.92828.bc. PMID 17272744. 
  20. ↑ "Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1". Annual Review of Cell and Developmental Biology 15: 551–78. 1999. doi:10.1146/annurev.cellbio.15.1.551. PMID 10611972. http://rsp.ima-press.net/rsp/article/view/2307. 
  21. ↑ "HIF-1: mediator of physiological and pathophysiological responses to hypoxia". Journal of Applied Physiology 88 (4): 1474–80. April 2000. doi:10.1152/jappl.2000.88.4.1474. PMID 10749844. 
  22. ↑ 22.0 22.1 22.2 "Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions". Experimental & Molecular Medicine 36 (1): 1–12. February 2004. doi:10.1038/emm.2004.1. PMID 15031665. 
  23. ↑ "HIF-1 and tumor progression: pathophysiology and therapeutics". Trends in Molecular Medicine 8 (4 Suppl): S62–7. 2002. doi:10.1016/s1471-4914(02)02317-1. PMID 11927290. 
  24. ↑ "A conserved family of prolyl-4-hydroxylases that modify HIF". Science 294 (5545): 1337–40. November 2001. doi:10.1126/science.1066373. PMID 11598268. Bibcode: 2001Sci...294.1337B. 
  25. ↑ 25.0 25.1 "C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation". Cell 107 (1): 43–54. October 2001. doi:10.1016/s0092-8674(01)00507-4. PMID 11595184. 
  26. ↑ "HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing". Science 292 (5516): 464–8. April 2001. doi:10.1126/science.1059817. PMID 11292862. Bibcode: 2001Sci...292..464I. 
  27. ↑ "Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation". Science 292 (5516): 468–72. April 2001. doi:10.1126/science.1059796. PMID 11292861. Bibcode: 2001Sci...292..468J. 
  28. ↑ 28.0 28.1 "Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation". The EMBO Journal 20 (18): 5197–206. September 2001. doi:10.1093/emboj/20.18.5197. PMID 11566883. 
  29. ↑ "Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit". The Journal of Biological Chemistry 271 (50): 32253–9. December 1996. doi:10.1074/jbc.271.50.32253. PMID 8943284. 
  30. ↑ "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. May 1997. doi:10.1073/pnas.94.11.5667. PMID 9159130. Bibcode: 1997PNAS...94.5667K. 
  31. ↑ "Induction of HIF-1alpha in response to hypoxia is instantaneous". FASEB Journal 15 (7): 1312–4. May 2001. doi:10.1096/fj.00-0732fje. PMID 11344124. 
  32. ↑ "Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL". Nature 417 (6892): 975–8. June 2002. doi:10.1038/nature00767. PMID 12050673. 
  33. ↑ 33.0 33.1 "Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling". Science 296 (5574): 1886–9. June 2002. doi:10.1126/science.1073440. PMID 12004076. Bibcode: 2002Sci...296.1886M. 
  34. ↑ 34.0 34.1 "Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch". Science 295 (5556): 858–61. February 2002. doi:10.1126/science.1068592. PMID 11823643. Bibcode: 2002Sci...295..858L. 
  35. ↑ "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". Molecular and Cellular Biology 22 (9): 2984–92. May 2002. doi:10.1128/mcb.22.9.2984-2992.2002. PMID 11940656. 
  36. ↑ "Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments" (in en). Molecular Therapy: Nucleic Acids 5 (9): e366. September 2016. doi:10.1038/mtna.2016.66. PMID 27673562. 
  37. ↑ eurekalert.org staff (3 June 2015). "Scientist at LIMR leads study demonstrating drug-induced tissue regeneration". Lankenau Institute for Medical Research (LIMR). http://www.eurekalert.org/pub_releases/2015-06/mlhl-sal060215.php. 
  38. ↑ "Drug-induced regeneration in adult mice". Science Translational Medicine 7 (290): 290ra92. June 2015. doi:10.1126/scitranslmed.3010228. PMID 26041709. 
  39. ↑ "Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α". Neuron 88 (4): 720–34. November 2015. doi:10.1016/j.neuron.2015.09.050. PMID 26526390. 
  40. ↑ "Intrinsic mechanisms of neuronal axon regeneration" (in En). Nature Reviews. Neuroscience 19 (6): 323–337. June 2018. doi:10.1038/s41583-018-0001-8. PMID 29666508. 
  41. ↑ "The Role of Hypoxia-Inducible Factor in Wound Healing". Advances in Wound Care 3 (5): 390–399. May 2014. doi:10.1089/wound.2013.0520. PMID 24804159. 
  42. ↑ "Skin patch could help heal, prevent diabetic ulcers, study finds" (in en). © Stanford University, Stanford, California 94305. 2015-01-23. https://biox.stanford.edu/highlight/skin-patch-could-help-heal-prevent-diabetic-ulcers-study-finds. 
  43. ↑ "Transdermal deferoxamine prevents pressure-induced diabetic ulcers". Proceedings of the National Academy of Sciences of the United States of America 112 (1): 94–9. January 2015. doi:10.1073/pnas.1413445112. PMID 25535360. Bibcode: 2015PNAS..112...94D. 
  44. ↑ "Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds". Journal of Controlled Release 308: 232–239. August 2019. doi:10.1016/j.jconrel.2019.07.009. PMID 31299261. https://pubmed.ncbi.nlm.nih.gov/31299261/. 
  45. ↑ "Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice". Wound Repair and Regeneration 26 (3): 300–305. May 2018. doi:10.1111/wrr.12667. PMID 30152571. 
  46. ↑ "Skin Rejuvenation through HIF-1α Modulation". Plastic and Reconstructive Surgery 141 (4): 600e–607e. April 2018. doi:10.1097/PRS.0000000000004256. PMID 29596193. https://pubmed.ncbi.nlm.nih.gov/29596193/. 
  47. ↑ "Deferiprone Stimulates Aged Dermal Fibroblasts Via HIF-1α Modulation". Aesthetic Surgery Journal 41 (4): 514–524. June 2020. doi:10.1093/asj/sjaa142. ISSN 1090-820X. PMID 32479616. https://pubmed.ncbi.nlm.nih.gov/32479616/. 
  48. ↑ "A single-center blinded randomized clinical trial to evaluate the anti-aging effects of a novel HSF™-based skin care formulation". Journal of Cosmetic Dermatology 19 (11): 2936–2945. November 2020. doi:10.1111/jocd.13356. PMID 32306525. 
  49. ↑ "Molecular Mechanisms of Hair Growth and Regeneration: Current Understanding and Novel Paradigms". Dermatology 236 (4): 271–280. 2020. doi:10.1159/000506155. PMID 32163945. 
  50. ↑ Tomorrowlabs. "Tomorrowlabs" (in en). https://www.tomorrowlabs.at/. 
  51. ↑ "Kosmetikbranche: Wie das Beauty-Start-up Tomorrowlabs den Markt erobert" (in de). https://www.handelsblatt.com/unternehmen/mittelstand/familienunternehmer/kosmetikbranche-wie-das-beauty-start-up-tomorrowlabs-den-markt-erobert/25523424.html. 
  52. ↑ "Ein Protein gegen das Altern und für das Geldverdienen" (in de). https://www.nachrichten.at/wirtschaft/wirtschaftsraumooe/ein-protein-gegen-das-altern-und-fuer-das-geldverdienen;art467,3277897. 
  53. ↑ "Das neue Beauty-Investment von Michael Pieper - HZ" (in de). https://www.handelszeitung.ch/unternehmen/das-neue-beauty-investment-von-michael-pieper. 
  54. ↑ andrea.hodoschek (2020-08-03). "Milliardenmarkt Anti-Aging: Start-up aus Österreich mischt mit" (in de). https://kurier.at/wirtschaft/wirtschaft-von-innen/milliardenmarkt-anti-aging-start-up-aus-oesterreich-mischt-mit/400989071. 
  55. ↑ "Regulation of hypoxia-inducible factor-1alpha by NF-kappaB". The Biochemical Journal 412 (3): 477–84. June 2008. doi:10.1042/BJ20080476. PMID 18393939. PMC 2474706. http://www.hif1.com. 
  56. ↑ Rius, J., Guma, M., Schachtrup, C. et al. 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
  57. ↑ "Hydroxylation of HIF-1: oxygen sensing at the molecular level". Physiology 19 (4): 176–82. August 2004. doi:10.1152/physiol.00001.2004. PMID 15304631. 
  58. ↑ 58.0 58.1 "The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain therapies". International Journal of Medical Sciences 10 (10): 1412–21. 2013. doi:10.7150/ijms.5630. PMID 23983604. 
  59. ↑ 59.0 59.1 "HIF-1 regulation: not so easy come, easy go". Trends in Biochemical Sciences 33 (11): 526–34. November 2008. doi:10.1016/j.tibs.2008.08.002. PMID 18809331. 
  60. ↑ 60.0 60.1 60.2 "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases". Cancer Research 59 (22): 5830–5. November 1999. PMID 10582706. 
  61. ↑ 61.0 61.1 "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. August 2000. doi:10.1016/s0002-9440(10)64554-3. PMID 10934146. 
  62. ↑ 62.0 62.1 "Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma". Cancer 97 (6): 1573–81. March 2003. doi:10.1002/cncr.11246. PMID 12627523. 
  63. ↑ 63.0 63.1 "Hypoxia in cancer: significance and impact on clinical outcome". Cancer and Metastasis Reviews 26 (2): 225–39. June 2007. doi:10.1007/s10555-007-9055-1. PMID 17440684. 
  64. ↑ 64.0 64.1 64.2 "Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma". Life Sciences 224: 169–176. May 2019. doi:10.1016/j.lfs.2019.03.056. PMID 30914315. https://www.sciencedirect.com/science/article/abs/pii/S0024320519302206. 
  65. ↑ "Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer". Cancer Research 61 (7): 2911–6. April 2001. PMID 11306467. 
  66. ↑ "Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects". Journal of the National Cancer Institute 93 (4): 266–76. February 2001. doi:10.1093/jnci/93.4.266. PMID 11181773. 
  67. ↑ "[Intravenous systemic thrombolysis using streptokinase in the treatment of developing cardiogenic shock in myocardial infarct]" (in cs). Vnitrni Lekarstvi 36 (5): 426–34. May 1990. PMID 2375073. 
  68. ↑ 68.0 68.1 68.2 "Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy". Clinical Cancer Research 7 (6): 1661–8. June 2001. PMID 11410504. 
  69. ↑ "Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance". Journal of Physiology and Biochemistry 77 (2): 249–260. May 2021. doi:10.1007/s13105-021-00791-3. PMID 33730333. https://pubmed.ncbi.nlm.nih.gov/33730333/. 
  70. ↑ "Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis". Journal of the National Cancer Institute 93 (4): 309–14. February 2001. doi:10.1093/jnci/93.4.309. PMID 11181778. 
  71. ↑ 71.0 71.1 "Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression". Cancer 88 (11): 2606–18. June 2000. doi:10.1002/1097-0142(20000601)88:11<2606::aid-cncr25>3.0.co;2-w. PMID 10861440. 
  72. ↑ "The contribution of proangiogenic factors to the progression of malignant disease: role of vascular endothelial growth factor and its receptors". Surgical Oncology Clinics of North America 10 (2): 339–56, ix. April 2001. doi:10.1016/S1055-3207(18)30069-3. PMID 11382591. 
  73. ↑ 73.0 73.1 "Hypoxia inducible factor-1alpha as a cancer drug target". Molecular Cancer Therapeutics 3 (5): 647–54. May 2004. doi:10.1158/1535-7163.647.3.5. PMID 15141023. 
  74. ↑ "Expression and distribution of vascular endothelial growth factor protein in human brain tumors". Acta Neuropathologica 93 (2): 109–17. February 1997. doi:10.1007/s004010050591. PMID 9039457. 
  75. ↑ 75.0 75.1 "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". Oncogene 19 (48): 5435–43. November 2000. doi:10.1038/sj.onc.1203938. PMID 11114720. 
  76. ↑ "Loss of PTEN facilitates HIF-1-mediated gene expression". Genes & Development 14 (4): 391–6. February 2000. doi:10.1101/gad.14.4.391. PMID 10691731. 
  77. ↑ "Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy.". Cancer Research 61 (5): 1830–2. March 2001. PMID 11280732. 
  78. ↑ "Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma". Autophagy 10 (1): 111–22. January 2014. doi:10.4161/auto.26838. PMID 24220190. 
  79. ↑ "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors". Proceedings of the National Academy of Sciences of the United States of America 95 (10): 5474–9. May 1998. doi:10.1073/pnas.95.10.5474. PMID 9576906. Bibcode: 1998PNAS...95.5474H. 
  80. ↑ "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". The Journal of Biological Chemistry 277 (12): 10236–43. March 2002. doi:10.1074/jbc.M110752200. PMID 11782478. 
  81. ↑ "Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300". The EMBO Journal 18 (7): 1905–14. April 1999. doi:10.1093/emboj/18.7.1905. PMID 10202154. 
  82. ↑ "Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1". Genes & Development 13 (1): 64–75. January 1999. doi:10.1101/gad.13.1.64. PMID 9887100. 
  83. ↑ 83.0 83.1 83.2 "Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel-Lindau recruitment and asparagine hydroxylation". Molecular Pharmacology 74 (1): 236–45. July 2008. doi:10.1124/mol.108.045278. PMID 18426857. 
  84. ↑ "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha". Proceedings of the National Academy of Sciences of the United States of America 99 (8): 5367–72. April 2002. doi:10.1073/pnas.082117899. PMID 11959990. Bibcode: 2002PNAS...99.5367F. 
  85. ↑ 85.0 85.1 "FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity". Genes & Development 15 (20): 2675–86. October 2001. doi:10.1101/gad.924501. PMID 11641274. 
  86. ↑ 86.0 86.1 "Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function". The Journal of Biological Chemistry 278 (16): 13595–8. April 2003. doi:10.1074/jbc.C200694200. PMID 12606552. 
  87. ↑ 87.0 87.1 "Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha". Genes & Development 14 (1): 34–44. January 2000. doi:10.1101/gad.14.1.34. PMID 10640274. 
  88. ↑ 88.0 88.1 88.2 "Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation". Experimental & Molecular Medicine 40 (1): 71–83. February 2008. doi:10.3858/emm.2008.40.1.71. PMID 18305400. 
  89. ↑ "Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53". Proceedings of the National Academy of Sciences of the United States of America 99 (16): 10305–9. August 2002. doi:10.1073/pnas.122347199. PMID 12124396. Bibcode: 2002PNAS...9910305H. 
  90. ↑ "Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha". Nature 392 (6674): 405–8. March 1998. doi:10.1038/32925. PMID 9537326. Bibcode: 1998Natur.392..405A. 
  91. ↑ "Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7". FEBS Letters 498 (1): 62–6. June 2001. doi:10.1016/S0014-5793(01)02499-1. PMID 11389899. 
  92. ↑ 92.0 92.1 "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Experimental & Molecular Medicine 40 (5): 479–85. October 2008. doi:10.3858/emm.2008.40.5.479. PMID 18985005. 
  93. ↑ 93.0 93.1 "Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha". The Journal of Biological Chemistry 283 (43): 29375–84. October 2008. doi:10.1074/jbc.M805919200. PMID 18694926. 
  94. ↑ "Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein". Nature Genetics 35 (3): 229–37. November 2003. doi:10.1038/ng1254. PMID 14556007. 
  95. ↑ "The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity". The EMBO Journal 22 (8): 1857–67. April 2003. doi:10.1093/emboj/cdg173. PMID 12682018. 
  96. ↑ "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein". The EMBO Journal 19 (16): 4298–309. August 2000. doi:10.1093/emboj/19.16.4298. PMID 10944113. 
  97. ↑ "HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation". Proceedings of the National Academy of Sciences of the United States of America 98 (17): 9630–5. August 2001. doi:10.1073/pnas.181341498. PMID 11504942. Bibcode: 2001PNAS...98.9630Y. 
  98. ↑ "The VHL tumor suppressor: master regulator of HIF". Current Pharmaceutical Design 15 (33): 3895–903. 2009. doi:10.2174/138161209789649394. PMID 19671042. 
  99. ↑ "Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1alpha in a cell-type-specific manner". The Journal of Neuroscience 30 (28): 9621–30. July 2010. doi:10.1523/JNEUROSCI.2295-10.2010. PMID 20631191. 
  100. ↑ "Anoxia ameliorates the dexamethasone-induced neurobehavioral alterations in the neonatal male rat pups". Hormones and Behavior 87: 122–128. January 2017. doi:10.1016/j.yhbeh.2016.11.013. PMID 27865789. 

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