HIF1A
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Location (UCSC) | Chr 14: 61.7 – 61.75 Mb | Chr 12: 73.95 – 73.99 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric
HIF1A is a
Structure
HIF1 is a
Gene and expression
The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1).
Function
The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals.
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
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.[44][45] 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.[46][47] HIF1A also controls skin healing.[48] 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.[49][50][51][52] Additionally the regenerative effect of HIF-1A modulation on aged skin cells was described[53][54] and a rejuvenating effect on aged facial skin was demonstrated in patients.[55] HIF modulation has also been linked to a beneficial effect on hair loss.[56] The biotech company Tomorrowlabs GmbH, founded in Vienna in 2016 by the physician Dominik Duscher and pharmacologist Dominik Thor, makes use of this mechanism.[57] Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.[58][59][60][61]
Regulation
HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an
PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as
Factors increasing HIF1A[66]
- Modulator of Degradation:
- Oxygen-Dependent:
- EPF UCP (degrades pHVL)
- VDU2 (de-ubiquitinates HIF1A)
- SUMOylation (via RSUME)
- DeSUMOylation ( via SENP1)
- Oxygen-independent:
- RACK1)
- Oxygen-Dependent:
- Modulators of translation:
Factors decreasing HIF1A[66]
Role in cancer
HIF1A is overexpressed in many human cancers.[67][68] HIF1A overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia.[69] Hypoxia promotes apoptosis in both normal and tumor cells.[70] However, hypoxic conditions in tumor microenvironment especially, along with accumulation of genetic alternations often contribute to HIF1A overexpression.[10]
Significant HIF1A expression has been noted in most solid tumors studied, which include cancers of the
Studies of[71] 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.
During hypoxia,
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.
Interactions
HIF1A has been shown to
See also
- Hypoxia inducible factors
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000100644 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021109 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ a b c "Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)".
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- ^ Tomorrowlabs. "Tomorrowlabs". Tomorrowlabs. Retrieved 2020-12-04.
- ^ "Kosmetikbranche: Wie das Beauty-Start-up Tomorrowlabs den Markt erobert". www.handelsblatt.com (in German). Retrieved 2020-12-04.
- ^ "Ein Protein gegen das Altern und für das Geldverdienen". nachrichten.at (in German). Retrieved 2020-12-04.
- ^ "Das neue Beauty-Investment von Michael Pieper - HZ". Handelszeitung (in German). Retrieved 2020-12-04.
- ^ andrea.hodoschek (2020-08-03). "Milliardenmarkt Anti-Aging: Start-up aus Österreich mischt mit". kurier.at (in German). Retrieved 2020-12-04.
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Further reading
- Semenza GL (August 2000). "HIF-1 and human disease: one highly involved factor". Genes & Development. 14 (16): 1983–91. S2CID 12788170.
- Semenza G (September 2002). "Signal transduction to hypoxia-inducible factor 1". Biochemical Pharmacology. 64 (5–6): 993–8. PMID 12213597.
- Arbeit JM (2002). "Quiescent hypervascularity mediated by gain of HIF-1 alpha function". Cold Spring Harbor Symposia on Quantitative Biology. 67: 133–42. PMID 12858534.
- Sitkovsky M, Lukashev D (September 2005). "Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors". Nature Reviews. Immunology. 5 (9): 712–21. S2CID 30400163.
- Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland JA (October 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". Histology and Histopathology. 20 (4): 1327–38. PMID 16136514.
- Schipani E (2006). "Hypoxia and HIF-1 alpha in chondrogenesis". Seminars in Cell & Developmental Biology. 16 (4–5): 539–46. PMID 16144691.
- Haase VH (August 2006). "Hypoxia-inducible factors in the kidney". American Journal of Physiology. Renal Physiology. 291 (2): F271–81. PMID 16554418.
- Liang D, Kong X, Sang N (November 2006). "Effects of histone deacetylase inhibitors on HIF-1". Cell Cycle. 5 (21): 2430–5. PMID 17102633.
External links
- Overview of all the structural information available in the PDB for UniProt: Q16665 (Human Hypoxia-inducible factor 1-alpha) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: Q61221 (Mouse Hypoxia-inducible factor 1-alpha) at the PDBe-KB.
- Scientific animation of HIF-1alpha in complex with ARNT on DNA: https://www.youtube.com/watch?v=azIEzLXXyHM