Hypoxia-inducible factors
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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]
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[edit] Structure
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
[edit] Members
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 |
[edit] Role
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. The hypoxia in wounds promotes the formation of blood vessels, but also the migration of keratinocytes and the restoration of the epithelium.[7]
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.
[edit] Mechanism
The alpha subunit of HIF-1 is a target for prolyl hydroxylation by HIF prolyl-hydroxylase, which makes HIF-1α a target for degradation by an E3 ubiquitin ligase, leading to quick degradation by the proteasome. This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited, since it utilizes oxygen as a cosubstrate.[8]
Hypoxia also results in a buildup of succinate, due to inhibition of the electron transport chain in the mitochondria. The buildup of succinate further inhibits HIF prolyl-hydroxylase action, since it is an end-product of HIF hydoxylation. In a similar manner, 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.[9]
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. [10]
[edit] Hypoxia-inducible factors as a therapeutic target
Recently several drugs have been developed which act as selective HIF prolyl-hydroxylase inhibitors.[11] The most notable of these include FibroGen's compounds FG-2216 and FG-4592,[12] [13]both intended as orally acting drugs for use in the treatment of forms of anemia.[14] By inhibiting HIF prolyl-hydroxylase, the activity of HIF-1α in the bloodstream is prolonged, which results in an increase in endogenous production of erythropoetin.[15] 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.[16]
In other scenarios and in contrast to the therapy outlined in the previous paragraph, 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. [10]
[edit] See also
[edit] References
- ^ 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 (inactive 2009-01-21). PMID 18410568.
- ^ 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:. PMID 7539918.
- ^ 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:. PMID 8663540.
- ^ 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:. PMID 9301332.
- ^ Ponting CP, Aravind L (November 1997). "PAS: a multifunctional domain family comes to light". Curr. Biol. 7 (11): R674–7. doi:. PMID 9382818.
- ^ 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:. PMID 16129688.
- ^ Benizri E, Ginouvès A, Berra E (April 2008). "The magic of the hypoxia-signaling cascade". Cellular and molecular life sciences : CMLS 65 (7-8): 1133–49. doi:. PMID 18202826.
- ^ Semenza GL (August 2004). "Hydroxylation of HIF-1: oxygen sensing at the molecular level". Physiology (Bethesda) 19: 176–82. doi:. PMID 15304631.
- ^ 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:. 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:. PMID 18393939. http://www.hif1.com.
- ^ 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:. 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. http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=3&p_RefId=3919.
- ^ 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:. PMID 17557894.
- ^ The FDA Accepts the Complete Response for Clinical Holds of FG-2216/FG-4592 for the Treatment of Anemia
[edit] External links
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