Oxygen plays a central role in the functioning of human cells: it is both essential for normal metabolism and toxic. Here we have annotated one aspect of cellular responses to oxygen, the role of hypoxia-inducible factor in regulating cellular transcriptional responses to changes in oxygen availability.
In the presence of oxygen members of the transcription factor family HIF-alpha, comprising HIF1A, HIF2A (EPAS1), and HIF3A, are hydroxylated on proline residues by PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) and on asparagine residues by HIF1AN (FIH) (reviewed in Pouyssegur et al. 2006, Semenza 2007, Kaelin and Ratcliffe 2008, Nizet and Johnson 2009, Brahimi-Horn and Pouyssegur 2009, Majmundar et al. 2010, Loenarz and Schofield 2011). Both types of reaction require molecular oxygen as a substrate and it is probable that at least some HIF-alpha molecules carry both hydroxylated asparagine and hydroxylated proline (Tian et al. 2011). Hydroxylated asparagine interferes with the ability of HIF-alpha to interact with p300 and CBP while hydroxylated proline facilitates the interaction of HIF-alpha with the E3 ubiquitin ligase VHL, causing ubiquitination and proteolysis of HIF-alpha. Hypoxia inhibits both types of hydroxylation, resulting in the stabilization of HIF-alpha, which then enters the nucleus, binds HIF-beta, and recruits p300 and CBP to activate target genes such as EPO and VEGF.
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Ivan M, Haberberger T, Gervasi DC, Michelson KS, Günzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG.; ''Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor.''; PubMedEurope PMCScholia
Chachami G, Paraskeva E, Mingot JM, Braliou GG, Görlich D, Simos G.; ''Transport of hypoxia-inducible factor HIF-1alpha into the nucleus involves importins 4 and 7.''; PubMedEurope PMCScholia
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Erbel PJ, Card PB, Karakuzu O, Bruick RK, Gardner KH.; ''Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor.''; PubMedEurope PMCScholia
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Wang GL, Semenza GL.; ''Purification and characterization of hypoxia-inducible factor 1.''; PubMedEurope PMCScholia
Tian H, McKnight SL, Russell DW.; ''Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.''; PubMedEurope PMCScholia
Dames SA, Martinez-Yamout M, De Guzman RN, Dyson HJ, Wright PE.; ''Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response.''; PubMedEurope PMCScholia
Bonicalzi ME, Groulx I, de Paulsen N, Lee S.; ''Role of exon 2-encoded beta -domain of the von Hippel-Lindau tumor suppressor protein.''; PubMedEurope PMCScholia
Depping R, Steinhoff A, Schindler SG, Friedrich B, Fagerlund R, Metzen E, Hartmann E, Köhler M.; ''Nuclear translocation of hypoxia-inducible factors (HIFs): involvement of the classical importin alpha/beta pathway.''; PubMedEurope PMCScholia
Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG.; ''Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.''; PubMedEurope PMCScholia
Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Bürgel T, Jelkmann W, Acker H, Fandrey J.; ''Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing.''; PubMedEurope PMCScholia
Foxler DE, Bridge KS, James V, Webb TM, Mee M, Wong SC, Feng Y, Constantin-Teodosiu D, Petursdottir TE, Bjornsson J, Ingvarsson S, Ratcliffe PJ, Longmore GD, Sharp TV.; ''The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.''; PubMedEurope PMCScholia
Kamura T, Maenaka K, Kotoshiba S, Matsumoto M, Kohda D, Conaway RC, Conaway JW, Nakayama KI.; ''VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.''; PubMedEurope PMCScholia
Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM.; ''Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor.''; PubMedEurope PMCScholia
Wang GL, Semenza GL.; ''General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.''; PubMedEurope PMCScholia
Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ.; ''Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK.; ''FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.''; PubMedEurope PMCScholia
Wang GL, Jiang BH, Rue EA, Semenza GL.; ''Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.''; PubMedEurope PMCScholia
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL.; ''Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.''; PubMedEurope PMCScholia
Zheng X, Ruas JL, Cao R, Salomons FA, Cao Y, Poellinger L, Pereira T.; ''Cell-type-specific regulation of degradation of hypoxia-inducible factor 1 alpha: role of subcellular compartmentalization.''; PubMedEurope PMCScholia
Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH.; ''Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.''; PubMedEurope PMCScholia
Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM.; ''An essential role for p300/CBP in the cellular response to hypoxia.''; PubMedEurope PMCScholia
Shioda T, Fenner MH, Isselbacher KJ.; ''msg1, a novel melanocyte-specific gene, encodes a nuclear protein and is associated with pigmentation.''; PubMedEurope PMCScholia
Huang LE, Ho V, Arany Z, Krainc D, Galson D, Tendler D, Livingston DM, Bunn HF.; ''Erythropoietin gene regulation depends on heme-dependent oxygen sensing and assembly of interacting transcription factors.''; PubMedEurope PMCScholia
Loenarz C, Schofield CJ.; ''Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases.''; PubMedEurope PMCScholia
Bruick RK, McKnight SL.; ''A conserved family of prolyl-4-hydroxylases that modify HIF.''; PubMedEurope PMCScholia
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG.; ''HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.''; PubMedEurope PMCScholia
Yu F, White SB, Zhao Q, Lee FS.; ''Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein.''; PubMedEurope PMCScholia
Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS.; ''A gain-of-function mutation in the HIF2A gene in familial erythrocytosis.''; PubMedEurope PMCScholia
Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA.; ''Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha.''; PubMedEurope PMCScholia
Lewis MD, Roberts BJ.; ''Role of nuclear and cytoplasmic localization in the tumour-suppressor activity of the von Hippel-Lindau protein.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Hu CJ, Sataur A, Wang L, Chen H, Simon MC.; ''The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha.''; PubMedEurope PMCScholia
Grabmaier K, A de Weijert MC, Verhaegh GW, Schalken JA, Oosterwijk E.; ''Strict regulation of CAIX(G250/MN) by HIF-1alpha in clear cell renal cell carcinoma.''; PubMedEurope PMCScholia
Lee S, Neumann M, Stearman R, Stauber R, Pause A, Pavlakis GN, Klausner RD.; ''Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein.''; PubMedEurope PMCScholia
Destruction of ubiquitinated HIF-alpha can occur in both the cytosol and nucleus (Berra et al. 2001). Upon reoxygenation of hypoxic cells HIF-alpha is ubiquitinated in the nucleus and transported to the cytosol in a complex with VHL:ElonginB:ElonginC:CUL2:RBX1 where it is destroyed (Groulx and Lee 2002, Jaakkola et al. 2001, Ivan et al. 2001)
HIF-alpha is translocated into the nucleus (Kallio et al. 1998, Depping et al. 2008, Chachami et al. 2009). Importin 4 and importin 7 (Chachami et al. 2009) as well as the importin alpha/beta pathway (Depping et al. 2008) appear to be capable of interacting with HIF-alpha. During hypoxia HIF-alpha accumulates in the nucleus where it associates with CBP and p300 (Kallio et al. 1998).
VHL is an E3 ubiquitin ligase that conjugates ubiquitin to hydroxylated HIF-alpha (Iwai et al. 1999, Kamura et al. 2000, Ohh et al. 2000, Groulx and Lee 2002, Maynard et al. 2003). VHL is predominantly cytosolic and shuttles between the cytosol and the nucleus (Lee et al. 1999, Groulx and Lee 2002). Ubiquitination and degradation of HIF-alpha can occur in both the cytosol and the nucleus (Berra et al. 2001).
HIF1AN (FIH, FIH-1) forms a homodimer that hydroxylates an asparagine residue on HIF1A and HIF2A (Hewitson et al. 2002, Lando et al. 2002, Metzen et al. 2003, Koivunen et al. 2004, Lancaster et al. 2004). The hydroxylation of the asparagine interferes with the interaction between HIF1A/HIF2A and p300, a histone acetylase, and therefore inhibits the ability of HIF1A/2A to activate transcription of target genes (Lando et al. 2002). Because molecular oxygen is a substrate of the reaction, hypoxia is a negative regulator of this reaction and thereby increases transcriptional activation of target genes by HIF1A/2A.
Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus (Metzen et al. 2003) hydroxylate HIF3A at proline-492 (Hirsila et al. 2003, Maynard et al. 2003). Note that proline-492 of the reference isoform is proline-490 in isoform 2, the protein cited by Maynard et al. 2003. The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to occur in the cytosol.
Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus hydroxylate HIF2A (EPAS1) at proline-405 and proline-531 (Hirsila et al. 2003, Percy et al. 2008, Furlow et al. 2009). The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to be cytosolic.
HIF (heterodimer of HIF-alpha and HIF-beta) recruits p300 and CBP to the promoters of target genes (Kallio et al. 1998, Ebert and Bunn 1998, Ema et al. 1999, Gu et al. 2001, Dames et al. 2002, Freedman et al. 2002).
The VHL component of the VHL:ElonginB:ElonginC:CUL2:RBX1 binds HIF-alpha that have hydroxylated proline residues (Cockman et al. 2000, Ohh et al. 2000, Tanimoto et al. 2000, Jaakkola et al. 2001, Ivan et al. 2001, Yu et al. 2001, Bonicalzi et al. 2001). The VHL:HIF-alpha complex is predominantly nuclear (Lewis and Roberts 2003) however binding and degradation of HIF-alpha can also occur in the cytosol (Berra et al. 2001).
HIF-alpha (HIF1A, HIF2A (EPAS1), HIF3A) forms a heterodimer with ARNT (HIF1-beta) (Wang et al. 1995, Jiang et al. 1996, Tian et al. 1997, Gu et al. 1998, Erbel et al. 2003).
VHL is an E3 ubiquitin ligase that conjugates ubiquitin to hydroxylated HIF-alpha (Iwai et al. 1999, Kamura et al. 2000, Ohh et al. 2000, Groulx and Lee 2002, Maynard et al. 2003). VHL is predominantly cytosolic and shuttles between the cytosol and the nucleus (Lee et al. 1999, Groulx and Lee 2002). Ubiquitination and degradation of HIF-alpha can occur in both the cytosol and the nucleus (Berra et al. 2001). Upon return to normoxia from hypoxia most ubiquitinated HIF-alpha is nuclear (Groulx and Lee 2002).
Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate HIF3A at proline-492 (Hirsila et al. 2003, Maynard et al. 2003). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008).
When hypoxic cells return to normoxia, HIF-alpha is ubiquitinated in the nucleus and exported to the cytosol (Groulx and Lee 2002). The shuttling of VHL between the nucleus and cytosol is required (Groulx and Lee 2002, Lee et al. 1999). Different cell types have different nucleocytoplasmic compartmentalization of HIF degradation (Zheng et al. 2006).
Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate HIF1A at proline-402 and proline-564 (Bruick and McKnight 2001, Jaakkola et al. 2001, Ivan et al. 2001, Ivan et al. 2002, Berra et al. 2003, Hirsila et al. 2003, Appelhoff et al. 2004, Tuckerman et al. 2004, Fedulova et al. 2007, Tian et al. 2011). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008). PHD1, PHD2, and PHD3 are each contained in a complex with LIMD1 and VHL (Foxler et al. 2012).
Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate EPAS1 (HIF2A) at proline-405 and proline-531 (Hirsila et al. 2003, Percy et al. 2008, Furlow et al. 2009). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008).
Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus (Metzen et al. 2003) hydroxylate HIF1A at proline-402 and proline-564 (Buick and McKnight 2001, Jaakkola et al. 2001, Ivan et al. 2001, Ivan et al. 2002, Berra et al. 2003, Hirsila et al. 2003, Appelhoff et al. 2004, Tuckerman et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to occur in the cytosol.
VHL within the VHL:ElonginB:ElonginC:CUL2:RBX1 Complex binds HIF-alpha subunits that have hydroxylated proline residues (Cockman et al. 2000, Ohh et al. 2000, Tanimoto et al. 2000, Jaakkola et al. 2001, Ivan et al. 2001, Yu et al. 2001). VHL constitutively shuttles between the cytosol and nucleoplasm (Lewis and Roberts 2003) and though the VHL:HIF-alpha complex is predominantly nuclear, binding and degradation can occur in both the cytosol and the nucleus (Berra et al. 2001).
The gene encoding carbonic anhydrase IX (CA9) is transcribed to yield mRNA and the mRNA is translated to yield protein. Hypoxia-inducible factor binds the promoter of CA9 and enhances expression of CA9.
The VEGFA (VEGF) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Hypoxia-inducible factor binds the VEGF promoter, recruits p300 and CBP, and enhances transcription.
The EPO gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of EPO is enhanced by Hypoxia-inducible factor, which binds to the EPO promoter.
The HIGD1A (RCF1A, HIG1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Ameri et al. 2015). Expression of HIGD1A is transactivated by HIF in response to hypoxia (Ameri et al. 2015).
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