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7  structures 122  species 3  interactions 301  sequences 18  architectures

Family: HIF-1a_CTAD (PF08778)

Summary: HIF-1 alpha C terminal transactivation domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Hypoxia-inducible factors". More...

Hypoxia-inducible factors Edit Wikipedia article

hypoxia-inducible factor 1, alpha subunit
Symbol HIF1A
Entrez 3091
HUGO 4910
OMIM 603348
RefSeq NM_001530
UniProt Q16665
Other data
Locus Chr. 14 q21-q24
aryl hydrocarbon receptor nuclear translocator
Symbol ARNT
Alt. symbols HIF1B, bHLHe2
Entrez 405
HUGO 700
OMIM 126110
RefSeq NM_001668
UniProt P27540
Other data
Locus Chr. 1 q21
endothelial PAS domain protein 1
Symbol EPAS1
Alt. symbols HIF2A, MOP2, PASD2, HLF
Entrez 2034
HUGO 3374
OMIM 603349
RefSeq NM_001430
UniProt Q99814
Other data
Locus Chr. 2 p21-p16
aryl-hydrocarbon receptor nuclear translocator 2
Symbol ARNT2
Alt. symbols HIF2B, KIAA0307, bHLHe1
Entrez 9915
HUGO 16876
OMIM 606036
RefSeq NM_014862
UniProt Q9HBZ2
Other data
Locus Chr. 1 q24
hypoxia-inducible factor 3, alpha subunit
Symbol HIF3A
Entrez 64344
HUGO 15825
OMIM 609976
RefSeq NM_152794
UniProt Q9Y2N7
Other data
Locus Chr. 19 q13

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia.[1][2]


Most, if not all, oxygen-breathing species express the highly conserved transcriptional complex HIF-1, which is a heterodimer composed of an alpha and a beta subunit, the latter being a constitutively-expressed aryl hydrocarbon receptor nuclear translocator (ARNT).[3][4] HIF-1 belongs to the PER-ARNT-SIM (PAS) subfamily of the basic helix-loop-helix (bHLH) family of transcription factors. The alpha and beta subunit are similar in structure and both contain the following domains:[5][6][7]

Hypoxia-inducible factor-1
PDB 1lm8 EBI.jpg
Structure of a HIF-1a-pVHL-ElonginB-ElonginC Complex.[8]
Symbol HIF-1
Pfam PF11413
HIF-1 alpha C terminal transactivation domain
PDB 1l3e EBI.jpg
Structure of hypoxia-inducible factor-1 alpha subunit.[9]
Symbol HIF-1a_CTAD
Pfam PF08778
InterPro IPR014887
SCOP 1l3e


The following are members of the human HIF family:

member gene protein
HIF-1α HIF1A hypoxia-inducible factor 1, alpha subunit
HIF-1β ARNT aryl hydrocarbon receptor nuclear translocator
HIF-2α EPAS1 endothelial PAS domain protein 1
HIF-2β ARNT2 aryl-hydrocarbon receptor nuclear translocator 2
HIF-3α HIF3A hypoxia inducible factor 3, alpha subunit
HIF-3β ARNT3 aryl-hydrocarbon receptor nuclear translocator 3


The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos and tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium.[10]

In general, HIFs are vital to development. In mammals, deletion of the HIF-1 genes results in perinatal death. HIF-1 has been shown to be vital to chondrocyte survival, allowing the cells to adapt to low-oxygen conditions within the growth plates of bones. HIF plays a central role in the regulation of human metabolism.[11]


The alpha subunits of HIF are hydroxylated at conserved proline residues by HIF prolyl-hydroxylases, allowing their recognition and ubiquitination by the VHL E3 ubiquitin ligase, which labels them for rapid degradation by the proteasome.[12] This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited, since it utilizes oxygen as a cosubstrate.[13]

Inhibition of electron transfer in the succinate dehydrogenase complex due to mutations in the SDHB or SDHD genes can cause a build-up of succinate that inhibits HIF prolyl-hydroxylase, stabilizing HIF-1α. This is termed pseudohypoxia.

HIF-1, when stabilized by hypoxic conditions, upregulates several genes to promote survival in low-oxygen conditions. These include glycolysis enzymes, which allow ATP synthesis in an oxygen-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIF-1 acts by binding to HIF-responsive elements (HREs) in promoters that contain the sequence NCGTG (where N is either A or G).

It has been shown that muscle A kinase–anchoring protein (mAKAP) organized E3 ubiquitin ligases, affecting stability and positioning of HIF-1 inside its action site in the nucleus. Depletion of mAKAP or disruption of its targeting to the perinuclear (in cardiomyocytes) region altered the stability of HIF-1 and transcriptional activation of genes associated with hypoxia. Thus, "compartmentalization" of oxygen-sensitive signaling components may influence the hypoxic response.[14]

The advanced knowledge of the molecular regulatory mechanisms of HIF1 activity under hypoxic conditions contrast sharply with the paucity of information on the mechanistic and functional aspects governing NF-κB-mediated HIF1 regulation under normoxic conditions. However, HIF-1α stabilization is also found in non-hypoxic conditions through an, until recently, unknown mechanism. It was shown that NF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression in the presence of normal oxygen pressure. siRNA (small interfering RNA) studies for individual NF-κB members revealed differential effects on HIF-1α mRNA levels, indicating that NF-κB can regulate basal HIF-1α expression. Finally, it was shown that, when endogenous NF-κB is induced by TNFα (tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner.[15] HIF-1 and HIF-2 have different physiological roles. HIF-2 regulates erythropoietin production in adult life.[16]

Repair or regeneration

In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF-1a via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of Hif-1a results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF-1a can either turn off, or turn on the key process of mammalian regeneration.[17][18]

As a therapeutic target


Recently, several drugs that act as selective HIF prolyl-hydroxylase inhibitors have been developed.[19][20] The most notable compounds are: Roxadustat (FG-4592);[21] Vadadustat (AKB-6548),[22] Daprodustat (GSK1278863),[23] Desidustat (ZYAN-1),[24] and Molidustat (Bay 85-3934),[25] all of which are intended as orally acting drugs for the treatment of anemia.[26] Other significant compounds from this family, which are used in research but have not been developed for medical use in humans, include MK-8617,[27] YC-1,[28] IOX-2,[29] 2-methoxyestradiol,[30] GN-44028,[31] AKB-4924,[32] Bay 87-2243,[33] FG-2216[34] and FG-4497.[35] By inhibiting prolyl-hydroxylase enzyme, the stability of HIF-2α in the kidney is increased, which results in an increase in endogenous production of erythropoietin.[36] Both FibroGen compounds made it through to Phase II clinical trials, but these were suspended temporarily in May 2007 following the death of a trial participant taking FG-2216 from fulminant hepatitis (liver failure), however it is unclear whether this death was actually caused by FG-2216. The hold on further testing of FG-4592 was lifted in early 2008, after the FDA reviewed and approved a thorough response from FibroGen.[37] Roxadustat, vadadustat, daprodustat and molidustat have now all progressed through to Phase III clinical trials for treatment of renal anemia.[21][22][23]

Inflammation and cancer

In other scenarios and in contrast to the therapy outlined above, recent research suggests that HIF induction in normoxia is likely to have serious consequences in disease settings with a chronic inflammatory component.[38][39][40] It has also been shown that chronic inflammation is self-perpetuating and that it distorts the microenvironment as a result of aberrantly active transcription factors. As a consequence, alterations in growth factor, chemokine, cytokine, and ROS balance occur within the cellular milieu that in turn provide the axis of growth and survival needed for de novo development of cancer and metastasis. These results have numerous implications for a number of pathologies where NF-κB and HIF-1 are deregulated, including rheumatoid arthritis and cancer.[41][42][43][44] Therefore, it is thought that understanding the cross-talk between these two key transcription factors, NF-κB and HIF, will greatly enhance the process of drug development.[15][45]

HIF activity is involved in angiogenesis required for cancer tumor growth, so HIF inhibitors such as phenethyl isothiocyanate and Acriflavine[46] are (since 2006) under investigation for anti-cancer effects.[47][48][49]


Research conducted on mice suggests that stabilizing HIF using an HIF prolyl-hydroxylase inhibitor enhances hippocampal memory, likely by increasing erythropoietin expression.[50] HIF pathway activators such as ML-228 may have neuroprotective effects and are of interest as potential treatments for stroke and spinal cord injury.[51][52]

See also


  1. ^ Smith TG, Robbins PA, Ratcliffe PJ (May 2008). "The human side of hypoxia-inducible factor". British Journal of Haematology. 141 (3): 325–34. doi:10.1111/j.1365-2141.2008.07029.x. PMC 2408651Freely accessible. PMID 18410568. 
  2. ^ Wilkins SE, Abboud MI, Hancock RL, Schofield CJ (April 2016). "Targeting Protein-Protein Interactions in the HIF System". ChemMedChem. 11 (8): 773–86. doi:10.1002/cmdc.201600012. PMC 4848768Freely accessible. PMID 26997519. 
  3. ^ Wang GL, Jiang BH, Rue EA, Semenza GL (June 1995). "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension". Proceedings of the National Academy of Sciences of the United States of America. 92 (12): 5510–4. doi:10.1073/pnas.92.12.5510. PMC 41725Freely accessible. PMID 7539918. 
  4. ^ Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (July 1996). "Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1". The Journal of Biological Chemistry. 271 (30): 17771–8. doi:10.1074/jbc.271.30.17771. PMID 8663540. 
  5. ^ Zhulin IB, Taylor BL, Dixon R (September 1997). "PAS domain S-boxes in Archaea, Bacteria and sensors for oxygen and redox". Trends in Biochemical Sciences. 22 (9): 331–3. doi:10.1016/S0968-0004(97)01110-9. PMID 9301332. 
  6. ^ Ponting CP, Aravind L (November 1997). "PAS: a multifunctional domain family comes to light". Current Biology. 7 (11): R674–7. doi:10.1016/S0960-9822(06)00352-6. PMID 9382818. 
  7. ^ Yang J, Zhang L, Erbel PJ, Gardner KH, Ding K, Garcia JA, Bruick RK (October 2005). "Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor". The Journal of Biological Chemistry. 280 (43): 36047–54. doi:10.1074/jbc.M501755200. PMID 16129688. 
  8. ^ Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich NP (June 2002). "Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling". Science. 296 (5574): 1886–9. doi:10.1126/science.1073440. PMID 12004076. 
  9. ^ Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ (April 2002). "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. doi:10.1073/pnas.082117899. PMC 122775Freely accessible. PMID 11959990. 
  10. ^ Benizri E, Ginouvès A, Berra E (April 2008). "The magic of the hypoxia-signaling cascade". Cellular and Molecular Life Sciences. 65 (7–8): 1133–49. doi:10.1007/s00018-008-7472-0. PMID 18202826. 
  11. ^ Formenti F, Constantin-Teodosiu D, Emmanuel Y, Cheeseman J, Dorrington KL, Edwards LM, Humphreys SM, Lappin TR, McMullin MF, McNamara CJ, Mills W, Murphy JA, O'Connor DF, Percy MJ, Ratcliffe PJ, Smith TG, Treacy M, Frayn KN, Greenhaff PL, Karpe F, Clarke K, Robbins PA (July 2010). "Regulation of human metabolism by hypoxia-inducible factor". Proceedings of the National Academy of Sciences of the United States of America. 107 (28): 12722–7. doi:10.1073/pnas.1002339107. PMC 2906567Freely accessible. PMID 20616028. 
  12. ^ Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (May 1999). "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis". Nature. 399 (6733): 271–5. doi:10.1038/20459. PMID 10353251. 
  13. ^ Semenza GL (August 2004). "Hydroxylation of HIF-1: oxygen sensing at the molecular level". Physiology. 19 (4): 176–82. doi:10.1152/physiol.00001.2004. PMID 15304631. 
  14. ^ Wong W, Goehring AS, Kapiloff MS, Langeberg LK, Scott JD (December 2008). "mAKAP compartmentalizes oxygen-dependent control of HIF-1alpha". Science Signaling. 1 (51): ra18. doi:10.1126/scisignal.2000026. PMC 2828263Freely accessible. PMID 19109240. 
  15. ^ a b van Uden P, Kenneth NS, Rocha S (June 2008). "Regulation of hypoxia-inducible factor-1alpha by NF-kappaB". The Biochemical Journal. 412 (3): 477–84. doi:10.1042/BJ20080476. PMC 2474706Freely accessible. PMID 18393939. 
  16. ^ Haase VH (July 2010). "Hypoxic regulation of erythropoiesis and iron metabolism". American Journal of Physiology. Renal Physiology. 299 (1): F1–13. doi:10.1152/ajprenal.00174.2010. PMC 2904169Freely accessible. PMID 20444740. 
  17. ^ staff (3 June 2015). "Scientist at LIMR leads study demonstrating drug-induced tissue regeneration". Lankenau Institute for Medical Research (LIMR),. Retrieved 3 July 2015. 
  18. ^ Zhang Y, Strehin I, Bedelbaeva K, Gourevitch D, Clark L, Leferovich J, Messersmith PB, Heber-Katz E (June 2015). "Drug-induced regeneration in adult mice". Science Translational Medicine. 7 (290): 290ra92. doi:10.1126/scitranslmed.3010228. PMC 4687906Freely accessible. PMID 26041709. 
  19. ^ Bruegge K, Jelkmann W, Metzen E (2007). "Hydroxylation of hypoxia-inducible transcription factors and chemical compounds targeting the HIF-alpha hydroxylases". Current Medicinal Chemistry. 14 (17): 1853–62. doi:10.2174/092986707781058850. PMID 17627521. 
  20. ^ Maxwell PH, Eckardt KU (March 2016). "HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond". Nature Reviews. Nephrology. 12 (3): 157–68. doi:10.1038/nrneph.2015.193. PMID 26656456. 
  21. ^ a b Becker K, Saad M (2017). "A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat". Advances in Therapy. 34 (4): 848–853. doi:10.1007/s12325-017-0508-9. PMID 28290095. 
  22. ^ a b Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH (2016). "Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease". Kidney International. 90 (5): 1115–1122. doi:10.1016/j.kint.2016.07.019. PMID 27650732. 
  23. ^ a b Ariazi JL, Duffy KJ, Adams DF, Fitch DM, Luo L, Pappalardi M, Biju M, DiFilippo EH, Shaw T, Wiggall K, Erickson-Miller C (2017). "Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia". The Journal of Pharmacology and Experimental Therapeutics. 363 (3): 336–347. doi:10.1124/jpet.117.242503. PMID 28928122. 
  24. ^ Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, Parikh DP, Heading H, Patel HB, Gupta RJ, Shah CY, Patel MR, Dholakia VN, Sukhadiya R, Jain MR, Parmar KV, Barot K (May 2017). "Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers". Clinical Pharmacokinetics. 57: 87–102. doi:10.1007/s40262-017-0551-3. PMID 28508936. 
  25. ^ Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U (2014). "Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects". PLOS One. 9 (11): e111838. doi:10.1371/journal.pone.0111838. PMC 4230943Freely accessible. PMID 25392999. 
  26. ^ Cases A (December 2007). "The latest advances in kidney diseases and related disorders". Drug News & Perspectives. 20 (10): 647–54. PMID 18301799. 
  27. ^ Debenham JS, Madsen-Duggan C, Clements MJ, Walsh TF, Kuethe JT, Reibarkh M, Salowe SP, Sonatore LM, Hajdu R, Milligan JA, Visco DM, Zhou D, Lingham RB, Stickens D, DeMartino JA, Tong X, Wolff M, Pang J, Miller RR, Sherer EC, Hale JJ (December 2016). "Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia". Journal of Medicinal Chemistry. 59 (24): 11039–11049. doi:10.1021/acs.jmedchem.6b01242. PMID 28002958. 
  28. ^ Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW (April 2003). "YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1". Journal of the National Cancer Institute. 95 (7): 516–25. doi:10.1093/jnci/95.7.516. PMID 12671019. 
  29. ^ Deppe J, Popp T, Egea V, Steinritz D, Schmidt A, Thiermann H, Weber C, Ries C (May 2016). "Impairment of hypoxia-induced HIF-1α signaling in keratinocytes and fibroblasts by sulfur mustard is counteracted by a selective PHD-2 inhibitor". Archives of Toxicology. 90 (5): 1141–50. doi:10.1007/s00204-015-1549-y. PMID 26082309. 
  30. ^ Wang R, Zhou S, Li S (2011). "Cancer therapeutic agents targeting hypoxia-inducible factor-1". Current Medicinal Chemistry. 18 (21): 3168–89. doi:10.2174/092986711796391606. PMID 21671859. 
  31. ^ Minegishi H, Fukashiro S, Ban HS, Nakamura H (February 2013). "Discovery of Indenopyrazoles as a New Class of Hypoxia Inducible Factor (HIF)-1 Inhibitors". ACS Medicinal Chemistry Letters. 4 (2): 297–301. doi:10.1021/ml3004632. PMC 4027554Freely accessible. PMID 24900662. 
  32. ^ Okumura CY, Hollands A, Tran DN, Olson J, Dahesh S, von Köckritz-Blickwede M, Thienphrapa W, Corle C, Jeung SN, Kotsakis A, Shalwitz RA, Johnson RS, Nizet V (September 2012). "A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection". Journal of Molecular Medicine. 90 (9): 1079–89. doi:10.1007/s00109-012-0882-3. PMC 3606899Freely accessible. PMID 22371073. 
  33. ^ Görtz GE, Horstmann M, Aniol B, Reyes BD, Fandrey J, Eckstein A, Berchner-Pfannschmidt U (December 2016). "Hypoxia-Dependent HIF-1 Activation Impacts on Tissue Remodeling in Graves' Ophthalmopathy-Implications for Smoking". The Journal of Clinical Endocrinology and Metabolism. 101 (12): 4834–4842. doi:10.1210/jc.2016-1279. PMID 27610652. 
  34. ^ Beuck S, Schänzer W, Thevis M (2012). "Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis". Drug Test Anal. 4: 830–45. doi:10.1002/dta.390. PMID 22362605. 
  35. ^ Silva PL, Rocco PR, Pelosi P (August 2015). "FG-4497: a new target for acute respiratory distress syndrome?". Expert Review of Respiratory Medicine. 9 (4): 405–9. doi:10.1586/17476348.2015.1065181. PMID 26181437. 
  36. ^ Hsieh MM, Linde NS, Wynter A, Metzger M, Wong C, Langsetmo I, Lin A, Smith R, Rodgers GP, Donahue RE, Klaus SJ, Tisdale JF (September 2007). "HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques". Blood. 110 (6): 2140–7. doi:10.1182/blood-2007-02-073254. PMC 1976368Freely accessible. PMID 17557894. 
  37. ^ The FDA Accepts the Complete Response for Clinical Holds of FG-2216/FG-4592 for the Treatment of Anemia
  38. ^ Eltzschig HK, Bratton DL, Colgan SP (November 2014). "Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases". Nature Reviews. Drug Discovery. 13 (11): 852–69. doi:10.1038/nrd4422. PMC 4259899Freely accessible. PMID 25359381. 
  39. ^ Salminen A, Kaarniranta K, Kauppinen A (August 2016). "AMPK and HIF signaling pathways regulate both longevity and cancer growth: the good news and the bad news about survival mechanisms". Biogerontology. 17 (4): 655–80. doi:10.1007/s10522-016-9655-7. PMID 27259535. 
  40. ^ Taylor CT, Doherty G, Fallon PG, Cummins EP (October 2016). "Hypoxia-dependent regulation of inflammatory pathways in immune cells". The Journal of Clinical Investigation. 126 (10): 3716–3724. doi:10.1172/JCI84433. PMC 5096820Freely accessible. PMID 27454299. 
  41. ^ Cummins EP, Keogh CE, Crean D, Taylor CT (2016). "The role of HIF in immunity and inflammation". Molecular Aspects of Medicine. 47–48: 24–34. doi:10.1016/j.mam.2015.12.004. PMID 26768963. 
  42. ^ Hua S, Dias TH (2016). "Hypoxia-Inducible Factor (HIF) as a Target for Novel Therapies in Rheumatoid Arthritis". Frontiers in Pharmacology. 7: 184. doi:10.3389/fphar.2016.00184. PMC 4921475Freely accessible. PMID 27445820. 
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  46. ^ Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL (October 2009). "Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization". Proceedings of the National Academy of Sciences of the United States of America. 106 (42): 17910–5. doi:10.1073/pnas.0909353106. PMC 2764905Freely accessible. PMID 19805192. 
  47. ^ Syed Alwi SS, Cavell BE, Telang U, Morris ME, Parry BM, Packham G (November 2010). "In vivo modulation of 4E binding protein 1 (4E-BP1) phosphorylation by watercress: a pilot study". The British Journal of Nutrition. 104 (9): 1288–96. doi:10.1017/S0007114510002217. PMC 3694331Freely accessible. PMID 20546646. 
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

HIF-1 alpha C terminal transactivation domain Provide feedback

Hypoxia inducible factor-1 alpha (HIF-1 alpha) is the regulatory subunit of the heterodimeric transcription factor HIF-1. It plays a key role in cellular response to low oxygen tension. This region corresponds to the C terminal transactivation domain.

Literature references

  1. Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ; , Proc Natl Acad Sci U S A. 2002;99:5367-5372.: Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha. PUBMED:11959990 EPMC:11959990

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR014887

Hypoxia inducible factor-1 alpha (HIF-1 alpha) is the regulatory subunit of the heterodimeric transcription factor HIF-1. It plays a key role in cellular response to low oxygen tension. This region corresponds to the C-terminal transactivation domain.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: pdb_1l3e
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Mistry J
Number in seed: 11
Number in full: 301
Average length of the domain: 36.80 aa
Average identity of full alignment: 73 %
Average coverage of the sequence by the domain: 4.39 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.1 25.1
Noise cut-off 24.7 23.8
Model length: 37
Family (HMM) version: 10
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


There are 3 interactions for this family. More...

Cupin_8 zf-TAZ zf-TAZ


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HIF-1a_CTAD domain has been found. There are 7 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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