同: hypoxic inducible factor

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/12/25 22:05:30」(JST)

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aryl-hydrocarbon receptor nuclear translocator 2
Identifiers
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
Identifiers
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 changes in available oxygen in the cellular environment, specifically, to decreases in oxygen, or hypoxia.^[1]

Structure[edit]

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).^[2]^[3] 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:^[4]^[5]^[6]

N-terminus – a bHLH domain for DNA binding
central region – Per-ARNT-Sim (PAS) domain which facilitates heterodimerization
C-terminus – recruits transcriptional coregulatory proteins

Hypoxia-inducible factor-1

Structure of a HIF-1a-pVHL-ElonginB-ElonginC Complex.^[7]

Identifiers

Symbol

HIF-1

Pfam

PF11413

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

HIF-1 alpha C terminal transactivation domain

Structure of hypoxia inducible factor-1 alpha subunit.^[8]

Identifiers

Symbol

HIF-1a_CTAD

Pfam

PF08778

InterPro

IPR014887

SCOP

1l3e

SUPERFAMILY

1l3e

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Members[edit]

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

Role[edit]

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 cancer tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium.^[9]

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.^[10]

Mechanism[edit]

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.^[11] This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited, since it utilizes oxygen as a cosubstrate.^[12]

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.

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.^[13]

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.^[14] HIF-1 and HIF-2 have different physiological roles. HIF-2 regulates erythropoietin production in adult life.^[15]

As a therapeutic target[edit]

Anemia[edit]

Recently several drugs have been developed which act as selective HIF prolyl-hydroxylase inhibitors.^[16] The most notable of these include FibroGen's compounds FG-2216 and FG-4592,^[17]^[18] both are intended as orally acting drugs for use in the treatment of forms of anemia.^[19] By inhibiting HIF prolyl-hydroxylase, the stability of HIF-2α in the kidney is increased, which results in an increase in endogenous production of erythropoietin.^[20] Both of these drugs made it through to phase II clinical trials, but these were suspended temporarily in May 2007 following the death of a trial participant from fulminant hepatitis. However it is unclear whether this death was caused by FG-2216. The hold has been lifted in early 2008 as FDA has reviewed and approved a thorough response from FibroGen.^[21]

Inflammation and cancer[edit]

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. 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. Consequently, 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. The results of a recently published study have numerous implications for a number of pathologies where NF-κB and HIF-1 are deregulated, including rheumatoid arthritis and cancer. 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.^[14]

HIF activity is involved in angiogenesis required for cancer tumor growth, so HIF inhibitors such as phenethyl isothiocyanate and Acriflavine^[22] are under investigation for anti-cancer effects.^[23]^[24]^[25]

Neurology[edit]

Research conducted on mice suggests that stabilizing HIF using an HIF prolyl-hydroxylase inhibitor enhances hippocampal memory, likely by increasing erythropoietin expression.^[26]

References[edit]

^ Smith TG, Robbins PA, Ratcliffe PJ (May 2008). "The human side of hypoxia-inducible factor". Br. J. Haematol. 141 (3): 325–34. doi:10.1111/j.1365-2141.2008.07029.x. PMC 2408651. PMID 18410568. Cite uses deprecated parameters (help)
^ 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". Proc. Natl. Acad. Sci. U.S.A. 92 (12): 5510–4. doi:10.1073/pnas.92.12.5510. PMC 41725. PMID 7539918. Cite uses deprecated parameters (help)
^ Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (July 1996). "Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1". J. Biol. Chem. 271 (30): 17771–8. doi:10.1074/jbc.271.30.17771. PMID 8663540. Cite uses deprecated parameters (help)
^ Zhulin IB, Taylor BL, Dixon R (September 1997). "PAS domain S-boxes in Archaea, Bacteria and sensors for oxygen and redox". Trends Biochem. Sci. 22 (9): 331–3. doi:10.1016/S0968-0004(97)01110-9. PMID 9301332. Cite uses deprecated parameters (help)
^ Ponting CP, Aravind L (November 1997). "PAS: a multifunctional domain family comes to light". Curr. Biol. 7 (11): R674–7. doi:10.1016/S0960-9822(06)00352-6. PMID 9382818. Cite uses deprecated parameters (help)
^ 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". J. Biol. Chem. 280 (43): 36047–54. doi:10.1074/jbc.M501755200. PMID 16129688. Cite uses deprecated parameters (help)
^ 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. Cite uses deprecated parameters (help)
^ Freedman SJ, Sun ZY, Poy F, et al. (April 2002). "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5367–72. doi:10.1073/pnas.082117899. PMC 122775. PMID 11959990. Cite uses deprecated parameters (help)
^ Benizri E, Ginouvès A, Berra E (April 2008). "The magic of the hypoxia-signaling cascade". Cell. Mol. Life Sci. 65 (7-8): 1133–49. doi:10.1007/s00018-008-7472-0. PMID 18202826. Cite uses deprecated parameters (help)
^ 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". Proc. Natl. Acad. Sci. U.S.A. 107 (28): 12722–7. doi:10.1073/pnas.1002339107. PMC 2906567. PMID 20616028. Cite uses deprecated parameters (help)
^ 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. Cite uses deprecated parameters (help)
^ Semenza GL (August 2004). "Hydroxylation of HIF-1: oxygen sensing at the molecular level". Physiology (Bethesda) 19 (4): 176–82. doi:10.1152/physiol.00001.2004. PMID 15304631. Cite uses deprecated parameters (help)
^ Wong W, Goehring AS, Kapiloff MS, Langeberg LK, Scott JD (2008). "mAKAP compartmentalizes oxygen-dependent control of HIF-1alpha". Sci Signal 1 (51): ra18. doi:10.1126/scisignal.2000026. PMC 2828263. PMID 19109240.
^ ^a ^b van Uden P, Kenneth NS, Rocha S (2008). "Regulation of hypoxia-inducible factor-1alpha by NF-kappaB". Biochem J. 412 (3): 477–484. doi:10.1042/BJ20080476. PMC 2474706. PMID 18393939.
^ Haase VH (July 2010). "Hypoxic regulation of erythropoiesis and iron metabolism". Am. J. Physiol. Renal Physiol. 299 (1): F1–13. doi:10.1152/ajprenal.00174.2010. PMC 2904169. PMID 20444740. Cite uses deprecated parameters (help)
^ Bruegge K, Jelkmann W, Metzen E (2007). "Hydroxylation of hypoxia-inducible transcription factors and chemical compounds targeting the HIF-alpha hydroxylases". Curr. Med. Chem. 14 (17): 1853–62. doi:10.2174/092986707781058850. PMID 17627521.
^ Dead URL FG-2216: Anemia
^ http://www.fibrogen.com/Anemia_Clinical_Studies
^ Cases A (December 2007). "The latest advances in kidney diseases and related disorders". Drug news & perspectives 20 (10): 647–54. ISSN 0214-0934. PMID 18301799. Cite uses deprecated parameters (help)
^ 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 1976368. PMID 17557894. Cite uses deprecated parameters (help)
^ The FDA Accepts the Complete Response for Clinical Holds of FG-2216/FG-4592 for the Treatment of Anemia
^ Lee, K.; Zhang, H.; Qian, D. Z.; Rey, S.; Liu, J. O.; Semenza, G. L. (2009). "Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization". Proceedings of the National Academy of Sciences 106 (42): 17910. doi:10.1073/pnas.0909353106. edit
^ 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". Br. J. Nutr. 104 (9): 1288–96. doi:10.1017/S0007114510002217. PMID 20546646. Cite uses deprecated parameters (help)
^ Semenza GL (October 2007). "Evaluation of HIF-1 inhibitors as anticancer agents". Drug Discov. Today 12 (19-20): 853–9. doi:10.1016/j.drudis.2007.08.006. PMID 17933687. Cite uses deprecated parameters (help)
^ Melillo G (September 2006). "Inhibiting hypoxia-inducible factor 1 for cancer therapy". Mol. Cancer Res. 4 (9): 601–5. doi:10.1158/1541-7786.MCR-06-0235. PMID 16940159. Cite uses deprecated parameters (help)
^ Adamcio, B.; Sperling, S.; Hagemeyer, N.; Walkinshaw, G.; Ehrenreich, H. (2010). "Hypoxia inducible factor stabilization leads to lasting improvement of hippocampal memory in healthy mice". Behavioural Brain Research 208 (1): 80–84. doi:10.1016/j.bbr.2009.11.010. PMID 19900484. edit

External links[edit]

Hypoxia-Inducible Factor 1 at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. フォンヒッペル・リンダウ病の分子生物学および病因 molecular biology and pathogenesis of von hippel lindau disease
2. 血管新生阻害剤の概要 overview of angiogenesis inhibitors
3. Chapter 6J：エリスロポエチン chapter 6j erythropoietin
4. バルトネラ属の基礎生物学 basic biology of bartonella species
5. 遺伝性腎癌症候群 hereditary kidney cancer syndromes

English Journal

Dexmedetomidine preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest.

Ding XD1, Zheng NN2, Cao YY1, Zhao GY1, Zhao P1.
The International journal of neuroscience.Int J Neurosci.2016 Mar;126(3):249-56. doi: 10.3109/00207454.2015.1005291. Epub 2015 Jul 14.
BACKGROUND/AIMS: To investigate the protection effect of dexmedetomidine preconditioning on global cerebral ischemic injury following asphyxial cardiac arrest (CA) in rats.METHODS: Seventy-two rats were randomly assigned into three groups, sham group (no asphyxia), control group (asphyxia only), and
PMID 25565380

Hypoxia inducible factor-1 mediates upregulation of urokinase-type plasminogen activator receptor gene transcription during hypoxia in cervical cancer cells.

Nishi H1, Sasaki T1, Nagamitsu Y1, Terauchi F1, Nagai T2, Nagao T2, Isaka K1.
Oncology reports.Oncol Rep.2016 Feb;35(2):992-8. doi: 10.3892/or.2015.4449. Epub 2015 Nov 25.
Hypoxia occurs during development of cervical cancer and is considered to correlate with its invasion. Hypoxia mediates tumor cells to have more invasive property in a variety of cancers. Urokinase plasminogen activator receptor (uPAR) which mediates invasion is considered to be induced by hypoxia.
PMID 26718775

Expression of hypoxia-inducible factor-1 by trophectoderm cells in response to hypoxia and epidermal growth factor.

Jeong W1, Bazer FW2, Song G3, Kim J4.
Biochemical and biophysical research communications.Biochem Biophys Res Commun.2016 Jan 8;469(2):176-82. doi: 10.1016/j.bbrc.2015.11.091. Epub 2015 Nov 24.
The low oxygen environment in the uterine environment requires pre-implantation embryos to adapt to oxygen deficiency. Hypoxia-inducible factor (HIF)-1 is a master regulator whereby cells adapt to changes in oxygen concentrations. In addition to hypoxic conditions, non-hypoxic stimuli such as growth
PMID 26620226

Japanese Journal

Enhancement of in vitro cell motility and invasiveness of human malignant pleural mesothelioma cells through the HIF-1 alpha-MUC1 pathway

Goudarzi Houman,Iizasa Hisashi,Furuhashi Masako,Nakazawa Seitaro,Nakane Rie,Liang Shanshan,Hida Yasuhiro,Yanagihara Kazuyoshi,Kubo Takanori,Nakagawa Koji,Kobayashi Masanobu,Irimura Tatsuro,Hamada Jun-ichi
Cancer letters 339(1), 82-92, 2013-10-01
… (2) this phenomenon resulted from increased expression of sialylated MUC1 through the activation of HIF-1 pathway; … (3) two HIF-binding sites located in the promoter region of MUC1 were important for MUC1 transactivation under hypoxia. …
NAID 120005345323

Hypoxia-Inducible Factors Activate CD133 Promoter through ETS Family Transcription Factors

Ohnishi Shunsuke,Maehara Osamu,Nakagawa Koji,Kameya Ayano,Otaki Kanako,Fujita Hirotoshi,Higashi Ryosuke,Takagi Kikuko,Asaka Masahiro,Sakamoto Naoya,Kobayashi Masanobu,Takeda Hiroshi
Plos one 8(6), e66255, 2013-06-20
… In this study, we analyzed the activity of five putative promoters (P1-P5) of CD133 in human embryonic kidney (HEK) 293 cells and colon cancer cell line WiDr, and found that the activity of promoters, particularly of P5, is elevated by overexpression of hypoxia-inducible factors (HIF-1 alpha and HIF-2 alpha). …
NAID 120005326763

Hypoxia-inducible factor1 alpha (HIF-1α) 新規ASVの発見

荒木章伍,久富寿
成蹊大学理工学研究報告 = The journal of the Faculty of Science and Technology, Seikei University 50(1), 51-52, 2013-06-00
NAID 120005305804

Related Pictures

HIF-1 HIF1A polymorphisms Transcription: HIF-1 Alpha: HIF-1 Alpha Hydroxylation of HIF-1: Oxygen Sensing at 図 HIF-1制御機構・例 hif 1 hif oxygen dependent hydroxylation in HIF - 1 |[alpha]| related 1 hif hif 1 hif 1 alpha hif 1

★リンクテーブル★

拡張検索	「HIF-1alpha」
関連記事	「H」「HI」

「HIF-1alpha」

endothelial PAS domain protein 1
Identifiers
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
Identifiers
Symbol	ARNT
Alt. symbols	HIF1B, bHLHe2
Entrez	405
HUGO	700
OMIM	126110
RefSeq	NM_001668
UniProt	P27540
Other data
Locus	Chr. 1 q21

hypoxia-inducible factor 1, alpha subunit
Identifiers
Symbol	HIF1A
Entrez	3091
HUGO	4910
OMIM	603348
RefSeq	NM_001530
UniProt	Q16665
Other data
Locus	Chr. 14 q21-q24

　　[★]

低酸素誘導因子1α

関: HIF1alpha、hypoxia-inducible factor 1alpha subunit

「H」

　　[★]

「HI」

　　[★] 赤血球凝集抑制試験　

[pmid18410568-1] Smith TG, Robbins PA, Ratcliffe PJ (May 2008). "The human side of hypoxia-inducible factor". Br. J. Haematol. 141 (3): 325–34. doi:10.1111/j.1365-2141.2008.07029.x. PMC 2408651. PMID 18410568. Cite uses deprecated parameters (help)

[pmid7539918-2] 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". Proc. Natl. Acad. Sci. U.S.A. 92 (12): 5510–4. doi:10.1073/pnas.92.12.5510. PMC 41725. PMID 7539918. Cite uses deprecated parameters (help)

[pmid8663540-3] Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (July 1996). "Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1". J. Biol. Chem. 271 (30): 17771–8. doi:10.1074/jbc.271.30.17771. PMID 8663540. Cite uses deprecated parameters (help)

[pmid9301332-4] Zhulin IB, Taylor BL, Dixon R (September 1997). "PAS domain S-boxes in Archaea, Bacteria and sensors for oxygen and redox". Trends Biochem. Sci. 22 (9): 331–3. doi:10.1016/S0968-0004(97)01110-9. PMID 9301332. Cite uses deprecated parameters (help)

[pmid9382818-5] Ponting CP, Aravind L (November 1997). "PAS: a multifunctional domain family comes to light". Curr. Biol. 7 (11): R674–7. doi:10.1016/S0960-9822(06)00352-6. PMID 9382818. Cite uses deprecated parameters (help)

[pmid16129688-6] 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". J. Biol. Chem. 280 (43): 36047–54. doi:10.1074/jbc.M501755200. PMID 16129688. Cite uses deprecated parameters (help)

[pmid12004076-7] 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. Cite uses deprecated parameters (help)

[pmid11959990-8] Freedman SJ, Sun ZY, Poy F, et al. (April 2002). "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5367–72. doi:10.1073/pnas.082117899. PMC 122775. PMID 11959990. Cite uses deprecated parameters (help)

[Benizri-9] Benizri E, Ginouvès A, Berra E (April 2008). "The magic of the hypoxia-signaling cascade". Cell. Mol. Life Sci. 65 (7-8): 1133–49. doi:10.1007/s00018-008-7472-0. PMID 18202826. Cite uses deprecated parameters (help)

[Formenti-10] 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". Proc. Natl. Acad. Sci. U.S.A. 107 (28): 12722–7. doi:10.1073/pnas.1002339107. PMC 2906567. PMID 20616028. Cite uses deprecated parameters (help)

[pmid10353251-11] 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. Cite uses deprecated parameters (help)

[pmid15304631-12] Semenza GL (August 2004). "Hydroxylation of HIF-1: oxygen sensing at the molecular level". Physiology (Bethesda) 19 (4): 176–82. doi:10.1152/physiol.00001.2004. PMID 15304631. Cite uses deprecated parameters (help)

[pmid19109240-13] Wong W, Goehring AS, Kapiloff MS, Langeberg LK, Scott JD (2008). "mAKAP compartmentalizes oxygen-dependent control of HIF-1alpha". Sci Signal 1 (51): ra18. doi:10.1126/scisignal.2000026. PMC 2828263. PMID 19109240.

[pmid18393939-14] van Uden P, Kenneth NS, Rocha S (2008). "Regulation of hypoxia-inducible factor-1alpha by NF-kappaB". Biochem J. 412 (3): 477–484. doi:10.1042/BJ20080476. PMC 2474706. PMID 18393939.

[pmid20444740-15] Haase VH (July 2010). "Hypoxic regulation of erythropoiesis and iron metabolism". Am. J. Physiol. Renal Physiol. 299 (1): F1–13. doi:10.1152/ajprenal.00174.2010. PMC 2904169. PMID 20444740. Cite uses deprecated parameters (help)

[pmid17627521-16] Bruegge K, Jelkmann W, Metzen E (2007). "Hydroxylation of hypoxia-inducible transcription factors and chemical compounds targeting the HIF-alpha hydroxylases". Curr. Med. Chem. 14 (17): 1853–62. doi:10.2174/092986707781058850. PMID 17627521.

[17] Dead URL FG-2216: Anemia

[18] ttp://www.fibrogen.com/Anemia_Clinical_Studies

[pmid18301799-19] Cases A (December 2007). "The latest advances in kidney diseases and related disorders". Drug news & perspectives 20 (10): 647–54. ISSN 0214-0934. PMID 18301799. Cite uses deprecated parameters (help)

[pmid17557894-20] 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 1976368. PMID 17557894. Cite uses deprecated parameters (help)

[21] The FDA Accepts the Complete Response for Clinical Holds of FG-2216/FG-4592 for the Treatment of Anemia

[22] Lee, K.; Zhang, H.; Qian, D. Z.; Rey, S.; Liu, J. O.; Semenza, G. L. (2009). "Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization". Proceedings of the National Academy of Sciences 106 (42): 17910. doi:10.1073/pnas.0909353106. edit

[pmid20546646-23] 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". Br. J. Nutr. 104 (9): 1288–96. doi:10.1017/S0007114510002217. PMID 20546646. Cite uses deprecated parameters (help)

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