The regulation mechanism of HIF–1 and its function in ischemic brain injury
Zhang Cuicui, Geng Deqin[dh1]
Department of Neurology of Affiliated Hospital of Xuzhou Medical College, Xuzhou City, Jiangsu Province, 221003
Jiangsu Key Laborotary of Brain Disease Bioinformation, Xuzhou City, Jiangsu Province, 221002
Abstract: Presently, there are more than 100 of genes directly regulated by HIF–1, involved in angiogenesis, erythropoiesis, energy metabolism, cell proliferation and apoptosis, tumor growth and metastasis, and resistance of tumor radiation and chemotherapy and many other aspects. Therefore, it is important to study the role of HIF–1 and its regulating mechanism.
Key words: HIF - 1; Cerebral ischemic diseases
Citation: Cuicui Z, Deqin G. Non-coding RNAs: new therapeutic targets and opportunities for hepatocellular carcinoma. J Gen Neuro 2016;
*Correspondence to:
Received: Accepted: Published Online:
Introduction
HIF–1 (hypoxia inducible factor 1 alpha, HIF–1) was discovered by Semenza et al. in 1992 while working on the gene expression of erythropoietin (EPO) in Hep3B cell line
[1]. Later, it was found that the factors can regulate various hypoxic reaction gene transcription and involve in the hypoxic response signal transduction process. Hence, it is named HIF-1
[2]. In this paper, the regulation of HIF-1 and its expression and significance in ischemic cerebrovascular diseases was reviewed.
The structure of HIF - 1
HIF-1 is a dimer composed of HIF–1α subunits and HIF–1β subunits. HIF–1α is the functional subunit while the HIF–1β is structural subunit. HIF–1α and HIF–1β protein contained spiral-ring structure, which can make the two subunits to form dimers and bind to DNA
[3]. Both of the subunits contain Per-ARNT-Sim (PAS) domain with a similar function. HIF-1α subunit contains oxygen-dependent degradation structural domain (ODDD) which can be hydroxylated by proline hydroxylase-2 (PHD–2) to damage HIF-1α subunits by protease when the oxygen content is normal
[4]. HIF-1α contains two active region (TAD) which is involved in regulating HIF-1genes for protein of interest. Two joint activator cAMP response element-binding (CREB) protein of HIF–1 can interact with HIF–1α's carboxyl terminal active region (C-TAD) by CREB-binding protein (CBP) and p300. These two activators are necessary for the transcription of HIF–1, and is also an effective target for HIF expression regulation. There is only one such similar area in HIF-1β and it is not necessary for the function of HIF–1 compound
[5].
Regulation of HIF–
1
The expression of HIF–1β is not affected by the oxygen content as its mRNA and protein levels were maintained at a stable level. While HIF-1α protein has a short half-life, it can only survive for up to 5 min, and is regulated by the oxygen level
[6]. The transcription and expression of HIF-1α are persistent, seems to be unaffected by oxygen content
[7]. However, under normal oxygen content, HIF-1α degrades very quickly that it cannot be measured. In the anoxic condition, HIF-1α become stable, enters the nucleus from the cytoplasm, and form dimers with HIF-1β. It should be noted that such type of HIF polymer has transcriptional activity
[8]. The activated HIF polymers combine with hers of regulating region of target genes, bind transfer rate activated substance, so as to induce gene expression
[9]. The regulation of the stability of HIF-1α and subsequent transcription activation is mainly affected by regulation of post-translational modifications, such as hydroxylation, protein phosphorylation, acetylation and phosphorylation.
The modification of HIF-1α occurs in several areas. Under constant oxygen condition, two proline residues in ODDD area of HIF-1α are hydroxylated, a lysine residue was acetylated, prompt to its interaction with von Hippel Lindau - (pVHL) ubiquitin E3 ligase complexes. pVHL will mark ubiquitin by HIF-1α, then degradate it by 26 s proteasome. The hydroxylation of asparagine residues of C -TAD also suppresses the combination of HIF-1α and CBP/p300, inhibiting the transcription activity of HIF–1
[10].
PHD proline amide hydroxylation role - ubiquitination signal
After cytoplasm HIF-1α generates, it would be located in ODDD through 2-keto glutaric acid family-dependent DAO existed in proline 402 (Pro402) and 564 (Pro564), make it rapidly hydroxylated
[11]. If two proline residues variate simultaneously, the interaction of HIF-1α and PVHL will be blocked. This can increase the stability of HIF-1α under oxygen condition. Even one proline residue variation can increase the stability of HIF-1α
[12].
HIF-1α oxidase is the end product of prolyl hydroxylase domain (PHD), HIF-proline hydroxylase (HPH) or Egg-layingnine (EGLN), and three other subtypes have been reported: PHD1/HPH3/EGLN2, PHD2/HPH2/EGLN1, and PHD3/HPH1/EGLN3 [13]. The biochemical characteristics of PHDs are similar with collagen proline-4-hydroxylase, is also 2- OG-dependent oxidase, need oxygen hydroxylation, at the same time, need Fe
2+ and vitamin C as a cofactor
[14]. However, the collagen proline-4-hydroxylase cannot catalyze HIF-1α/HIF-2α hydroxylation. The hydroxylation process decomposes oxygen as one oxygen atom is transferred to proline residue while the other one reacts with 2-OG to produce succinate and CO
2 [11]. Passivation of PHDs by 2-OG analogue can extend the half-life of HIF-1α
[15]. Fe
2+ existed in PHDs active site loosely combines with two histidine residues and a NMDA, forming 2-histidine-1-carboxylate coordination sequence. Iron and metal chelating agent (such as Co
2+, Ni
2-, and Mn
2+) can be used as reducing enzyme for Fe
2+ or even to replace Fe
2+ in combining Fe
2+ binding sites which have the effect of alpha stable HIF-1α, proving the PHDs demand for Fe
2+ [11,16]. Vitamin C can sustain bivalent iron ion (Fe
2+) state, is crucial to maintain and achieve PHDs active state
[17].
In vitro three potential hydroxylation of PHDs HIF-alpha following abilities PHD2 insight PHD3 > PHD1, PHD2 in carrier cells, control HIF-1 alpha outcome of critical speed
[4]. Small interference RNA with specificity can knock out PHD2 in stable oxygen andHIF-1α levels, meanwhile small interfering RNA silencing PHD1 or PHD3 cannot have a similar effect
[18]. And, with slight oxygen change, the mRNA of PHD2 and protein was induced while the mRNA of PHD3 were raised, and PHD1 has no change
[19]. This could be a kind of self expression regulation of HIF-1α. In low oxygen situation, the SIAH1 and SIAH2, PHD1 and PHD3 specificity E3 ligase's expression level is raised to control the degradation of PHDs by proteasome
[20]. When transfection cell marker protein is excessive expressed, PHD2 was found first positioning in cytoplasm, and PHD1 is located in the nucleus while PHD3 is both of above
[19]. Although PHD2 is first located in cytoplasm, it can move through the cytoplasm and nucleus, so that the degradation of HIF-1α (in two parts) is achieved. Although these three enzymes are widely expressed in many organizations, they have tissue specificity excessive expression. The expression of PHD2 in fat tissue is the most
[21], as PHD3 mostly expressed in the heart and the placenta, and PHD1 has a high expression in testis
[22]. Different activity of PHDs enzyme, subcellular localization and the distribution of tissue may make responses to low oxygen levels has grade and tissue specificity. Many proteins such as OS-9, produced a lot of unknown function gene expression and it has been proven that proline hydroxylation promoted by HIF-1α and PHDs, can increase oxygen dependent HIF-1α degradation
[23]. Moreover, many second messengers also been shown to modify the activity of PHDs
[24].
PHDs are active in the presence of oxygen and may hydroxylate proline of HIF-1α, constituting of pVHL binded identification signal and the next ubiquitination, followed by degradation of HIF-1α
[25]. On the other hand, under deprived oxygen condition, there is no enzyme activation, hydroxylation modification, no pVHL/HIF binding was observed. Thus, HIF-1α is stable and accumulated in a cell. Full demand for oxygen implies the oxygen sensor effects on the PHDs in a cell
[26].
Ubiquitination of pVHL - degradation signaling pathways
At the moment where two proline residue of HIF-1α are decorated by hydroxylation, then pVHL captures hif-1α to form pVHL/HIF-1α complex. X-ray crystallography research shows that there is a surface pocket in pVHL, where hydroxyproline can be closely chimeric with it, and all the binding site structure are highly specific
[27]. Elongin pVHL proteins, elongin C, B, cullin-2, and Rbx1 form VCB-Cul2 E3 ligase complex. HIF-1 alpha at the E3 more protein complexes binding causes HIF-1 alpha times in protein function through the final degradation by proteasome. Nevertheless, the precise ubiquitination mechanism of lysine residues is still not clear.
pVHL is described for the first time in von Hippel Lindau-(VHL) disease, is a human legacy of the tumor syndrome characterized by multiple tumors, such as clear cell renal carcinoma, pheochromocytoma, retinal cell tumor and central nervous system into blood vessels
[28]. VHL gene encoding length (213 amino acids) and N end short protein (54-213 amino acids). As two proteins showed a similar function, they are often called pVHL. The mutated VHL gene, as a product of tumor suppressor gene function was found in these diseases
[29, 30]. In the conditions of absence of the wild type pVHL cells, the HIF-1α and HIF-2α are stable and active when oxygen levels is normal. The effect is shown through excessive gene expression induced by hypoxia
[31]. The function of pVHL is recovered through stable transfection, reversing protein stability and genetic abnormalities
[31]. PVHL gene mutations cause tumor formation, therefore, may be the mechanism of HIF alpha under normal oxygen environment as the stability and activity of angiogenesis factors led to the subsequent coding gene expression. This shows that its role has prevailed even before the cells are exposed to hypoxia environment.
PVHL E3 ligase complex is ubiquitous in different combinations, mainly concentrated in the cytoplasm. It shuttles within the cytoplasm and nucleus, leading to degradation of HIF-1α of cytoplasm and nucleus
[32,33]. However, the pVHL dependent signal pathway may not be the only way to cause HIF-1α degradation. With increasing level of pVHL, a large number of other proteins was reported to affect HIF-1 alpha times in terms of protein function and stability. For example, Carcinogenic E3 ubiquitin ligase rats double microbody 2 (MDM2) which has been considered alpha can cause p53 dependent way HIF-1 times in protein function
[34]. The Jab1 as c-Jun and junD transcription and auxiliary activators, proves again that low oxygen increases HI -1 alpha level, may compete with p53 in combination with HIF-1 alpha
[35]. And pVHL also proved with other HIF-1 signaling pathways of protein interaction and regulation might not ensure the stability of HIF-1 alpha.
Combination of pVHL is promoted by lysine through ARD1 acetylation
The ODDD area lysine residues with positioning HIF-1α was called arrest-defective-1 (ARD1) acetyltransferase acetylation
[36]. ARD1 were first discovered in yeast and its name is derived from the defective yeast cell mitosis. Lys532 acetylation affects the HIF-1 alpha and pVHL interaction leading to the instability of HIF-1 alpha
[37]. The Lys532 variation for arginine HIF-1α stability increased
[38]. The HIF-1 alpha protein levels were determined by acetyl called butyric acid enzyme inhibitors that maintain and increase the HIF-1 alpha acetylation status
[39]. As the acetyl transferase activity is not affected by oxygen content, ARD1 may activate and acetylate HIF-1α, regardless to oxygen level. However, in conditions of low oxygen where ARD1's mRNA and protein levels are low, low acetylation of HIF-1α is expected under low oxygen conditions
[37].
CBP/p300 binding is blocked by aspartic acid through hydroxylation of FIH-1
The above HIF-1α modification after translation adjusts the stability of HIF-1α protein. However, slight stability is not sufficient for HIF-1 transcription activation. The second main mechanism of control HIF activation is through adjusting its activation domains N-TAD and C-TAD. These areas act by transcription of auxiliary activation factor such as CBP/p300, SRC-1, and TIF2
[40]. Under normal oxygen tension, the inhibition of HIF-1 protein (factor inhibiting HIF-1, FHI) in HIF-1 alpha CTD asparagine residues 803 (Asn803) hydroxylation (in HIF-2 alpha Asn851), deters the interaction of HIF-1 alpha with CBP/p300
[41]. Hypoxia can cancel asparagine hydroxylation, and allow alpha HIF- 1 C–TAD to combine with CBP/p300 specific sites thus, activating gene transcription
[42]. The alanine replacement with Asn803 in oxygen condition often reduce HIF-1 alpha and antioxidant levels
[43]. And reports show that FIH-1 and pVHL combine to form ternary complex with HIF-1α
[44]. Although for the activity of FHI-1 and pVHL interaction is not required, providing that the histone acetyl off pVHL enzyme interferes with the transcription process, the adjustment of FIH-1 HIF-1 alpha is turned on
[41]. FIH-1 mainly exist in the cytoplasm, but seems that some parts also exists in the nucleus
[19]. The transcription of FIH-1 is not dependent on the oxygen concentration, and does not affect the stability of HIF-1α
[19]. Similar to PHD, asparagine acyl hydroxylase FIH - 1 is 2-OG dependent oxidase, also need Fe
2+ and vitamin C as a cofactor
[10]. Using oxygen as a prosthetic group, FIH-1 can be used as the second oxygen sensor.
Activation is enhanced through MAPK phosphorylation
Although hydroxylase is crucial to sense oxygen tension and regulate the activity of HIF-1, there is another control mechanism of HIF-1. The importance of protein phosphorylation as a control activity is well known. The direct phosphorylation of HIF-1α has been reported and mitogen-activated protein kinases(MAPK) pathway seems to account for a major role
[45]. P42/44 and p38 kinase can phosphorylate HIF-1α/HIF-2α in vitro
[46]. Moreover, p42/44 and p38 kinase inhibitors blocked HIF-1α mediated gene expression
[47]. Transfection activity forms of p42/44 kinase can stimulate HIF-1 alpha transcription activity without affecting the stability of HIF-1 alpha. Subsequently, the alpha/HIF HIF-1-2 alpha during hypoxia changes the p42/44 MAPK
[47]. The phosphorylated does not affect the stability of HIF-1 alpha and DNA binding
[48]. One of the explanations for this incidence is that HIF-1β has priority to combine with phosphorylated HIF-1α
[49]. Although function related phosphorylation sites still needs to be identified, the threonine 796 of HIF-1α and threonine 844 of HIF-2α can be possible sites.
Expression and significance of HIF-1 in ischemic cerebrovascular disease
Ischemia hypoxia is common in stroke, and studies have shown that different types cells of different areas of the brain have the expression of HIF-1α, during ischemia-reperfusion in rats
[50]. The current research shows that HIF-1α has a dual function of neural protection and apoptosis in the central nervous system. The survival may be related to the type of cell, ischemia time and pathological stimulus
[51].
Protection function of HIF-1 on cerebral ischemia
Study of low oxygen protection rats with cerebral ischemia found that the low oxygen can increase the expression of HIF-1 to relieve cerebral edema, reduce blood-brain barrier permeability. HIF-1 can improve cerebral anoxia tolerance. Deferoxamine, an iron chelating agent, can increase the stability of HIF-1α and act on the cells in order to enhance the expression of HIF-1α. According to the results, the brain damage area of ischemia rats treated with deferoxamine is reduced by 28%, and with improved capacity. Neurological score and sensorimotor skills recover early
[52]. Studies have shown that HIF target genes such as EPO and VEGF can inhibit apoptosis and protect the brain tissue. VEGF is the purpose gene of HIF-1. After cerebral ischemia injury, VEGF are expressed in radial glial cells, neurons, and endothelial cells
[53]. VEGF released after cerebral ischemia, play multiple roles through the membrane receptor VEGFR2. Neural precursor cells express VEGFR2 and VEGF by activating VEGF2 stimulating neurogenesis. The endogenous and exogenous VEGF can promote neurogenesis in a stroke model
[54]. The nerve cell in vitro experiments show that VEGF by induction of neuronal progenitor cells - Mash1 bHLH gene may induce the differentiation of neurons
[55]. At the same time, VEGF can promote the formation of capillaries collateral circulation after ischemia and increases oxygen tension. Vascular endothelial growth factor (Erythropoietin, EPO) is an early response factors after ischemia. Studies have shown that the effect of EPO may be related to inhibition of excitatory amino acids nerve toxicity along with free radical and resistance to apoptosis. At the same time, EPO is significant to the regeneration of neurons. Studies have shown that exogenous EPO can promote regeneration of neurons stroke
[56]. The neural cells in vitro experiments show that the differentiation of neurons can be promoted through stimulus of EPO by kinase Akt
[57].
The apoptosis is promoted by HIF-1
Study shows HIF-1αsiRNA effect can reduce the infarction area thus, reducing mortality
[58]. The application of HIF-1α activation drugs are also able to protect neurons in vitro and carrier of oxygen
[59]. This shows that HIF-1 can promote oxygen when the cell death. So, how does HIF-1 play the role of promoting apoptosis? Studies have shown that death due to cerebral ischemia is associated with the activation of microglia. In microglia, HIF-1 alpha to hypoxia induced, as excessive expression of iNOS play a regulatory role, and the excessive expression of iNOS, will activate the nitrogen oxide (NO) production which indirectly promotes the death of neurons
[60]. Studies have also shown that HIF-1 alpha from somatic cells can promote apoptosis by regulating gene to promote cell death. Caspase is an important material mediated apoptosis, Alain
[61] and other research has shown that after ischemia alpha and procaspase HIF-1-3 increased performance, showed the similar trend. The activated caspase 3 can be seen in cell expressed by HIF-1α. Electrophoresis tests showed that HIF-1α binding activated the promoter of caspase HIF-1-3 which will lead to apoptosis. Studies in rats have shown that after ischemia, apoptosis regulating factors BNIP3 can be detected in cortex neurons and striatum
[62]. BNIP3 is a member of the family of the BCL-2, and associated with immune response caused by ischemia and late-onset cell death. The well known BNIP3 HRE sequence in genes combines with HRE HIF-1 to start the gene expression while excessive expression of BNIP3 promotes cell death
[63].
4. Conclusion
To sum up, under the condition of constant oxygen, HIF-1 continues to express but soon degrades. However, when tissue or cell hypoxia occurs, the HIF-1α stability and transfer rate activity improved significantly. The regulation of the stability of HIF-1α and subsequent transcription activation is mainly affected by regulation of post-translational modifications, such as hydroxylation, protein phosphorylation, acetylation and phosphorylation. The expression of HIF-1 alpha increased significantly in hypoxic ischemic cerebrovascular disease. Nevertheless, its plays a dual role of protection while promoting the apoptosis of neurons. The conditions which will make hif-1α to protect and promote apoptosis role, simultaneously is still unclear. At the same time, recent studies have shown that BNIP3 mediated cells necrosis apoptosis (Necroptosis) is a form similar to necrosis for the regulation of cell death
[64]. The results Prompt HIF-1α may mediate apoptosis of other modes of cell death. The continuous improvement in research on the function and its mechanism of HIF-1α will provide new theoretical basis and therapeutic targets for the treatment of ischemic brain injury.
References
1. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12(12): 5447-5454. doi.org/10.1128/MCB.12.12.5447.
2. Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993; 268: 21513-21518.
3. Yang J, Zhang L, Erbel PJ, Gardner KH, Ding K, et al. Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor. J Biol Chem 2005; 280 (43): 36047-36054. doi.org/10.1074/jbc.M501755200.
4. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A, 1998; 95(14):7987-7992. doi.org/10.1073/pnas.95.14.7987.
5. Dery MA, Michaud MD, Richard DE. Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 2005; 37 (3): 535-450. doi.org/10.1016/j.biocel.2004.08.012.
6. Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 1997, 272 (36): 22642-22647. doi.org/10.1074/jbc.272.36.22642.
7. Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood 1998; 92(7): 2260-2268.
8. Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L. Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci USA 1997, 94 (11): 5667-7562.
9. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 2002, 2002; 295 (5556): 858-861. doi.org/10.1126/science.1068592.
10. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002; 16(12): 1466-1471. doi.org/10.1101/gad.991402.
11. Masson N, Ratcliffe PJ. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J Cell Sci 2003; 116 (15): 3041-3049. doi.org/10.1242/jcs.00655.
12. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. et al. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 2001; 20 (18): 5197-5206. doi.org/10.1242/jcs.00655.
13. Huang J, Zhao Q, Mooney SM, Lee FS. Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem 2002; 277(42):39792-39800. doi.org/10.1074/jbc.M206955200.
14. Schofield CJ, Zhang Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struct Biol 1999; 9(6):722-731. doi.org/10.1016/S0959-440X(99)00036-6.
15. Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A 2002; 99(21):13459-13464. doi.org/10.1073/pnas.192342099.
16. Yuan Y, Hilliard G, Ferguson T, Millhorn DE et al. Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J Biol Chem 2003; 278 (18): 15911-15916. doi.org/10.1074/jbc.M300463200.
17. Bruick RK, Mcknight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294 (5545):1337-1340. doi.org/10.1126/science.1066373.
18. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 2003; 22 (16):4082-4090. doi.org/10.1093/emboj/cdg392.
19. Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, et al. Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci 2003; 116 (7):1319-1326. doi.org/10.1242/jcs.00318.
20. Nakayama K, Ronai Z. Siah: new players in the cellular response to hypoxia. Cell Cycle 2004; 3(11):1345-1347. doi.org/10.4161/cc.3.11.1207.
21. Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, et al. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun, 2002, 296(2): 343-349. doi.org/10.1016/S0006-291X(02)00862-8.
22. Lieb ME, Menzies K, Moschella MC, Ni R, Taubman MB. Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. Biochem Cell Biol, 2002, 80: 421-426. doi.org/10.1139/o02-115.
23. Baek JH, Mahon PC, Oh J, Kelly B, Krishnamachary B, et al. OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Mol Cell 2005,17 (4) :503-512. .doi.org/10.1016/j.molcel.2005.01.011.
24. Temes E, Martin-Puig S, Acosta-Iborra B, Castellanos MC, Feijoo-Cuaresma M, et al.. Activation of HIF-prolyl hydroxylases by R59949, an inhibitor of the diacylglycerol kinase. J Biol Chem 2005, 280(25): 24238-24344. doi.org/10.1074/jbc.M414694200.
25. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292 (5516): 468-472. doi.org/10.1126/science.1059796.
26. Epstein AC, Gleadle JM, Mcneill LA, Hewitson KS, O'Rourke J, et al. C. Elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001, 107(1):43-54. doi.org/10.1016/S0092-8674(01)00507-4.
27. Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 2002,417 (6892):975-978. doi.org/10.1038/nature00767.
28. Ivan M, Kaelin WG Jr. The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev 2001; 11(1): 27-34. doi.org/10.1016/S0959-437X(00)00152-0.
29. Iliopoulos O, Ohh M, Kaelin WG Jr. PVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A 1998; 95(20): 11661-11666. doi.org/10.1073/pnas.95.20.11661.
30. Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A 1998; 95(15): 8817-8822. doi.org/10.1073/pnas.95.15.8817.
31. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A 1996; 93(20): 10595-10599. doi.org/10.1073/pnas.93.20.10595.
32. Berra E, Milanini J, Richard DE, Le Gall M, Vinals F, et al. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol 2000; 60(8): 1171-1178. doi.org/10.1016/S0006-2952(00)00423-8.
33. Groulx I, Lee S. Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein. Mol Cell Biol 2002; 22(15): 5319-5336. doi.org/10.1128/MCB.22.15.5319-5336.2002.
34. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 2000;14 (1):34-44.
35. Bae MK, Ahn MY, Jeong JW, Bae MH, Lee YM, et al. Jab1 interacts directly with HIF-1alpha and regulates its stability. J Biol Chem 2002; 277(1): 9-12. doi.org/10.1074/jbc.C100442200.
36. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, et al. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 2002; 111(5): 709-720. doi.org/10.1016/S0092-8674(02)01085-1.
37. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, et al. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 2002, 111(5):709-720. doi.org/10.1016/S0092-8674(02)01085-1.[dh2]
38. Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 2000; 19(16): 4298-309. doi.org/10.1093/emboj/19.16.4298.
39. Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 2001; 7(4): 437-443. doi.org/10.1038/86507.
40. Carrero P, Okamoto K, Coumailleau P, O-Brien S, Tanaka H, et al. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Mol Cell Biol 2000; 20(1):402-415. doi.org/10.1128/MCB.20.1.402-415.2000.
41. Hewitson KS, mcneill LA, Riordan MV, Tian YM, Bullock AN, et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 2002; 277 (29):26351-26355. doi.org/10.1074/jbc.C200273200.
42. Lando D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev, 2002; 16:1466-14471. doi.org/10.1101/gad.991402.
43. Lando D, Peet DJ, Whelan DA, et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 2002; 295:858-61.
[dh3]
44. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001; 15(20): 2675-2686. doi.org/10.1101/gad.924501.
45. Minet E, Michel G, Mottet D, Raes M, Mischiels. Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation. Free Radic Biol Med 2001; 31(7):847-855. doi.org/10.1016/S0891-5849(01)00657-8.
46. Sodhi A, Montaner S, Patel V, Zohar M, Bais C, et al. The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res 2000; 60(17): 4873-4880.
47. Hur E, Chang KY, Lee E, Lee SK, Park H. Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1alpha. Mol Pharmacol 2001; 59(5):1216-1224.
48. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. P42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 1999; 274(46):32631-32637. doi.org/10.1074/jbc.274.46.32631.
49. Suzuki H, Tomida A, Tsuruo T. Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 2001; 20(41):5779-5788. doi.org/10.1038/sj.onc.1204742.
50. Chavez JC, Agani F, Pichiule P, LaManna JC. Expression of hypoxia-inducible factor-1alpha in the brain of rats during chronic hypoxia. J Appl Physiol, 2000, 89(5):1937-1942.
51. Vangeison G, Carr D, Federoff HJ, Rempe DA. The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes. J Neurosci 2008; 28(8):1988-1993. doi.org/10.1523/JNEUROSCI.5323-07.2008.
52. Freret T, Valable S, Chazalviel L, Saulnier R, Mackenzie ET, et al. Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral ischemia in the rat. Eur J Neurosci 2006; 23(7):1757-1765. doi.org/10.1111/j.1460-9568.2006.04699.x.
53. Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 2006; 12(4):441-445. doi.org/10.1038/nm1387.
54. Wang Y, Jin K, Mao XO, Xie L, Banwait S, et al. VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration. J Neurosci Res 2007; 85(4):740-747. doi.org/10.1002/jnr.21169.
55. Chen J, Zacharek A, Li A, Zhang C, Ding J, et al. Vascular endothelial growth factor mediates atorvastatin-induced mammalian achaete-scute homologue-1 gene expression and neuronal differentiation after stroke in retired breeder rats. Neuroscience 2006; 141(2):737-744. doi.org/10.1016/j.neuroscience.2006.04.042.
56. Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, et al. Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 2000; 48(3):285-296. doi.org/10.1002/1531-8249(200009)48:3 <285::AID-ANA2>3.0.CO;2-8.
57. Wang L, Zhang ZG, Zhang RL, Jiao ZX, Wang Y, et al. Neurogenin 1 mediates erythropoietin enhanced differentiation of adult neural progenitor cells. J Cereb Blood Flow Metab 2006, 26(4):556-564. doi.org/10.1038/sj.jcbfm.9600215.
58. Chen C, Hu Q, Yan J, Yang X, Shi X, et al. Early inhibition of HIF-1alpha with small interfering RNA reduces ischemic-reperfused brain injury in rats. Neurobiol Dis 2009; 33(3):509-517. doi.org/10.1016/j.nbd.2008.12.010.
59. Baranova O, Miranda LF, Pichiule P, Dragatsis I, Johnson RS, et al. Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci, 2007, 27(23):6320-6332. doi.org/10.1523/JNEUROSCI.0449-07.2007.
60. Lu DY, Liou HC, Tang CH, Fu WM. Hypoxia-induced inos expression in microglia is regulated by the PI3-kinase/Akt/mtor signaling pathway and activation of hypoxia inducible factor-1alpha. Biochem Pharmacol 2006; 72(8):992-1000. doi.org/10.1016/j.bcp.2006.06.038.
61. Van Hoecke M, Prigent-Tessier AS, Garnier PE, Bertrand NM, Filomenako R, et al. Evidence of HIF-1 functional binding activity to caspase-3 promoter after photothrombotic cerebral ischemia. Mol Cell Neurosci 2007; 34(1):40-47. doi.org/10.1016/j.mcn.2006.09.009.
62. Althaus J, Bernaudin M, Petit E, Toutain J, Touzani O, et al. Expression of the gene encoding the pro-apoptotic BNIP3 protein and stimulation of hypoxia-inducible factor-1alpha (HIF-1alpha) protein following focal cerebral ischemia in rats. Neurochem Int 2006; 48(8):687-695. doi.org/10.1016/j.neuint.2005.12.008.
63. Baranova O, Miranda LF, Pichiule P, Dragatsis I, Johnson RS, et al. Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci, 2007; 27(23):6320-6332. doi.org/10.1523/JNEUROSCI.0449-07.2007.[dh4]
64. Xu X, Chua CC, Kong J, Kostrzewa RM, Kumaraguru U, et al. Necrostatin-1 protects against glutamate-induced glutathione depletion and caspase-independent cell death in HT-22 cells. J Neurochem 2007; 103(5): 2004-2014. doi.org/10.1111/j.1471-4159.2007.04884.x.
