Full text data of EGLN2
EGLN2
(EIT6)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Egl nine homolog 2; 1.14.11.29 (Estrogen-induced tag 6; HPH-3; Hypoxia-inducible factor prolyl hydroxylase 1; HIF-PH1; HIF-prolyl hydroxylase 1; HPH-1; Prolyl hydroxylase domain-containing protein 1; PHD1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Egl nine homolog 2; 1.14.11.29 (Estrogen-induced tag 6; HPH-3; Hypoxia-inducible factor prolyl hydroxylase 1; HIF-PH1; HIF-prolyl hydroxylase 1; HPH-1; Prolyl hydroxylase domain-containing protein 1; PHD1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00074957
IPI00074957 Egl nine homolog 2 Hypoxia-inducible factor prolyl hydroxylase 1, Functions as a cellular oxygen sensor and, under normoxic conditions, targets HIF through the hydroxylation for proteasomal degradation soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Cytoplasmic and nuclear n/a expected molecular weight found in band found in band 98 kdDa
IPI00074957 Egl nine homolog 2 Hypoxia-inducible factor prolyl hydroxylase 1, Functions as a cellular oxygen sensor and, under normoxic conditions, targets HIF through the hydroxylation for proteasomal degradation soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Cytoplasmic and nuclear n/a expected molecular weight found in band found in band 98 kdDa
UniProt
Q96KS0
ID EGLN2_HUMAN Reviewed; 407 AA.
AC Q96KS0; A8K5S0; Q8WWY4; Q9BV14;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Egl nine homolog 2;
DE EC=1.14.11.29;
DE AltName: Full=Estrogen-induced tag 6;
DE AltName: Full=HPH-3;
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 1;
DE Short=HIF-PH1;
DE Short=HIF-prolyl hydroxylase 1;
DE Short=HPH-1;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 1;
DE Short=PHD1;
GN Name=EGLN2; Synonyms=EIT6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P43).
RX PubMed=11574160; DOI=10.1016/S0378-1119(01)00633-3;
RA Taylor M.S.;
RT "Characterization and comparative analysis of the EGLN gene family.";
RL Gene 275:125-132(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P43), AND INDUCTION.
RC TISSUE=Mammary cancer;
RX PubMed=11850811; DOI=10.1038/sj.onc.1205113;
RA Seth P., Krop I., Porter D., Polyak K.;
RT "Novel estrogen and tamoxifen induced genes identified by SAGE (Serial
RT Analysis of Gene Expression).";
RL Oncogene 21:836-843(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Fetal brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Endometrium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Lung, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP REVIEW.
RX PubMed=11595178; DOI=10.1016/S0092-8674(01)00518-9;
RA Semenza G.L.;
RT "HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the
RT nucleus.";
RL Cell 107:1-3(2001).
RN [9]
RP FUNCTION, AND MUTAGENESIS OF HIS-358.
RX PubMed=11595184; DOI=10.1016/S0092-8674(01)00507-4;
RA Epstein A.C.R., Gleadle J.M., McNeill L.A., Hewitson K.S.,
RA O'Rourke J., Mole D.R., Mukherji M., Metzen E., Wilson M.I.,
RA Dhanda A., Tian Y.M., Masson N., Hamilton D.L., Jaakkola P.,
RA Barstead R., Hodgkin J., Maxwell P.H., Pugh C.W., Schofield C.J.,
RA Ratcliffe P.J.;
RT "C. elegans EGL-9 and mammalian homologs define a family of
RT dioxygenases that regulate HIF by prolyl hydroxylation.";
RL Cell 107:43-54(2001).
RN [10]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12163023; DOI=10.1016/S0006-291X(02)00862-8;
RA Oehme F., Ellinghaus P., Kolkhof P., Smith T.J., Ramakrishnan S.,
RA Huetter J., Schramm M., Flamme I.;
RT "Overexpression of PH-4, a novel putative proline 4-hydroxylase,
RT modulates activity of hypoxia-inducible transcription factors.";
RL Biochem. Biophys. Res. Commun. 296:343-349(2002).
RN [11]
RP MUTAGENESIS OF HIS-297; ASP-299; HIS-358 AND ARG-367.
RX PubMed=12039559; DOI=10.1016/S0960-894X(02)00219-6;
RA McNeill L.A., Hewitson K.S., Gleadle J.M., Horsfall L.E., Oldham N.J.,
RA Maxwell P.H., Pugh C.W., Ratcliffe P.J., Schofield C.J.;
RT "The use of dioxygen by HIF prolyl hydroxylase (PHD1).";
RL Bioorg. Med. Chem. Lett. 12:1547-1550(2002).
RN [12]
RP FUNCTION, AND SUBSTRATE RECOGNITION MOTIF.
RX PubMed=12181324; DOI=10.1074/jbc.M206955200;
RA Huang J., Zhao Q., Mooney S.M., Lee F.S.;
RT "Sequence determinants in hypoxia-inducible factor-1alpha for
RT hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3.";
RL J. Biol. Chem. 277:39792-39800(2002).
RN [13]
RP SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=12615973; DOI=10.1242/jcs.00318;
RA Metzen E., Berchner-Pfannschmidt U., Stengel P., Marxsen J.H.,
RA Stolze I., Klinger M., Huang W.Q., Wotzlaw C., Hellwig-Burgel T.,
RA Jelkmann W., Acker H., Fandrey J.;
RT "Intracellular localisation of human HIF-1 alpha hydroxylases:
RT implications for oxygen sensing.";
RL J. Cell Sci. 116:1319-1326(2003).
RN [14]
RP INDUCTION, AND SUBSTRATE SPECIFICITY.
RX PubMed=15247232; DOI=10.1074/jbc.M406026200;
RA Appelhoff R.J., Tian Y.M., Raval R.R., Turley H., Harris A.L.,
RA Pugh C.W., Ratcliffe P.J., Gleadle J.M.;
RT "Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3
RT in the regulation of hypoxia-inducible factor.";
RL J. Biol. Chem. 279:38458-38465(2004).
RN [15]
RP FUNCTION, INTERACTION WITH SIAH2, ALTERNATIVE INITIATION, INDUCTION,
RP AND MUTAGENESIS OF MET-1 AND MET-34.
RX PubMed=16509823; DOI=10.1042/BJ20051996;
RA Tian Y.M., Mole D.R., Ratcliffe P.J., Gleadle J.M.;
RT "Characterization of different isoforms of the HIF prolyl hydroxylase
RT PHD1 generated by alternative initiation.";
RL Biochem. J. 397:179-186(2006).
RN [16]
RP FUNCTION.
RX PubMed=17114296; DOI=10.1073/pnas.0602235103;
RA Cummins E.P., Berra E., Comerford K.M., Ginouves A., Fitzgerald K.T.,
RA Seeballuck F., Godson C., Nielsen J.E., Moynagh P., Pouyssegur J.,
RA Taylor C.T.;
RT "Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving
RT insight into hypoxia-induced NFkappaB activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18154-18159(2006).
RN [17]
RP SUBCELLULAR LOCATION.
RX PubMed=19631610; DOI=10.1016/j.bbrc.2009.07.090;
RA Steinhoff A., Pientka F.K., Mockel S., Kettelhake A., Hartmann E.,
RA Kohler M., Depping R.;
RT "Cellular oxygen sensing: Importins and exportins are mediators of
RT intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2.";
RL Biochem. Biophys. Res. Commun. 387:705-711(2009).
RN [18]
RP SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS OF LYS-102; ARG-106;
RP ARG-113; ARG-119 AND ARG-134.
RX PubMed=19339211; DOI=10.1016/j.bbamcr.2009.01.014;
RA Yasumoto K., Kowata Y., Yoshida A., Torii S., Sogawa K.;
RT "Role of the intracellular localization of HIF-prolyl hydroxylases.";
RL Biochim. Biophys. Acta 1793:792-797(2009).
RN [19]
RP SUBSTRATE SPECIFICITY, AND MASS SPECTROMETRY.
RX PubMed=21410436; DOI=10.1042/BJ20101201;
RA Pappalardi M.B., McNulty D.E., Martin J.D., Fisher K.E., Jiang Y.,
RA Burns M.C., Zhao H., Ho T., Sweitzer S., Schwartz B., Annan R.S.,
RA Copeland R.A., Tummino P.J., Luo L.;
RT "Biochemical characterization of human HIF hydroxylases using HIF
RT protein substrates that contain all three hydroxylation sites.";
RL Biochem. J. 436:363-369(2011).
RN [20]
RP INTERACTION WITH LIMD1; WTIP AND AJUBA.
RX PubMed=22286099; DOI=10.1038/ncb2424;
RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C.,
RA Feng Y., Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J.,
RA Ingvarsson S., Ratcliffe P.J., Longmore G.D., Sharp T.V.;
RT "The LIMD1 protein bridges an association between the prolyl
RT hydroxylases and VHL to repress HIF-1 activity.";
RL Nat. Cell Biol. 14:201-208(2012).
RN [21]
RP FUNCTION.
RX PubMed=23932902; DOI=10.1016/j.devcel.2013.06.014;
RA Moser S.C., Bensaddek D., Ortmann B., Maure J.F., Mudie S., Blow J.J.,
RA Lamond A.I., Swedlow J.R., Rocha S.;
RT "PHD1 links cell-cycle progression to oxygen sensing through
RT hydroxylation of the centrosomal protein Cep192.";
RL Dev. Cell 26:381-392(2013).
CC -!- FUNCTION: Cellular oxygen sensor that catalyzes, under normoxic
CC conditions, the post-translational formation of 4-hydroxyproline
CC in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a
CC specific proline found in each of the oxygen-dependent degradation
CC (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A.
CC Also hydroxylates HIF2A. Has a preference for the CODD site for
CC both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for
CC proteasomal degradation via the von Hippel-Lindau ubiquitination
CC complex. Under hypoxic conditions, the hydroxylation reaction is
CC attenuated allowing HIFs to escape degradation resulting in their
CC translocation to the nucleus, heterodimerization with HIF1B, and
CC increased expression of hypoxy-inducible genes. EGLN2 is involved
CC in regulating hypoxia tolerance and apoptosis in cardiac and
CC skeletal muscle. Also regulates susceptibility to normoxic
CC oxidative neuronal death. Links oxygen sensing to cell cycle and
CC primary cilia formation by hydroxylating the critical centrosome
CC component CEP192 which promotes its ubiquitination and subsequent
CC proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB
CC activation in hypoxic conditions. Target proteins are
CC preferencially recognized via a LXXLAP motif.
CC -!- CATALYTIC ACTIVITY: Hypoxia-inducible factor-L-proline + 2-
CC oxoglutarate + O(2) = hypoxia-inducible factor-trans-4-hydroxy-L-
CC proline + succinate + CO(2).
CC -!- COFACTOR: Binds 1 Fe(2+) ion per subunit.
CC -!- COFACTOR: Ascorbate.
CC -!- SUBUNIT: Interacts (preferably isoform p40) with SIAH2; the
CC interaction targets both SIAH2 isoforms for proteasomal
CC degradation in vitro. Interacts with LIMD1, WTIP and AJUBA.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=p43; Synonyms=PHD1p43;
CC IsoId=Q96KS0-1; Sequence=Displayed;
CC Name=p40; Synonyms=PHD1p40;
CC IsoId=Q96KS0-2; Sequence=VSP_038836;
CC -!- TISSUE SPECIFICITY: Expressed in adult and fetal heart, brain,
CC liver, lung, skeletal muscle, and kidney. Also expressed in testis
CC and placenta. Highest levels in adult brain, placenta, lung,
CC kidney, and testis. Expressed in hormone responsive tissues,
CC including normal and cancerous mammary, ovarian and prostate
CC epithelium.
CC -!- INDUCTION: By estrogen. Isoform p43 is induced by hypoxia leading
CC to protein stability. Isoform p40 repressed by hypoxia. Both
CC isoforms are induced by proteasomal inhibitor MG132 (at protein
CC level).
CC -!- DOMAIN: The Beta(2)beta(3) 'finger-like' loop domain is important
CC for substrate (HIFs' CODD/NODD) selectivity (By similarity).
CC -!- SIMILARITY: Contains 1 Fe2OG dioxygenase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH01723.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; AJ310544; CAC42510.1; -; mRNA.
DR EMBL; AY040565; AAK82943.1; -; mRNA.
DR EMBL; AK291385; BAF84074.1; -; mRNA.
DR EMBL; AL832506; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC008537; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471126; EAW57008.1; -; Genomic_DNA.
DR EMBL; BC001723; AAH01723.1; ALT_INIT; mRNA.
DR EMBL; BC036051; AAH36051.1; -; mRNA.
DR RefSeq; NP_444274.1; NM_053046.3.
DR RefSeq; NP_542770.2; NM_080732.3.
DR RefSeq; XP_005258526.1; XM_005258469.1.
DR RefSeq; XP_005258527.1; XM_005258470.1.
DR RefSeq; XP_005258528.1; XM_005258471.1.
DR UniGene; Hs.515417; -.
DR UniGene; Hs.631539; -.
DR UniGene; Hs.730737; -.
DR ProteinModelPortal; Q96KS0; -.
DR SMR; Q96KS0; 176-387.
DR IntAct; Q96KS0; 5.
DR MINT; MINT-1186497; -.
DR STRING; 9606.ENSP00000307080; -.
DR BindingDB; Q96KS0; -.
DR ChEMBL; CHEMBL3028; -.
DR DrugBank; DB00126; Vitamin C.
DR PhosphoSite; Q96KS0; -.
DR DMDM; 32129513; -.
DR PaxDb; Q96KS0; -.
DR PRIDE; Q96KS0; -.
DR DNASU; 112398; -.
DR Ensembl; ENST00000303961; ENSP00000307080; ENSG00000269858.
DR Ensembl; ENST00000406058; ENSP00000385253; ENSG00000269858.
DR Ensembl; ENST00000593726; ENSP00000469686; ENSG00000269858.
DR Ensembl; ENST00000594140; ENSP00000472414; ENSG00000269858.
DR GeneID; 112398; -.
DR KEGG; hsa:112398; -.
DR UCSC; uc002opg.4; human.
DR CTD; 112398; -.
DR GeneCards; GC19P041304; -.
DR HGNC; HGNC:14660; EGLN2.
DR MIM; 606424; gene.
DR neXtProt; NX_Q96KS0; -.
DR PharmGKB; PA27671; -.
DR eggNOG; COG3751; -.
DR HOGENOM; HOG000013099; -.
DR HOVERGEN; HBG051456; -.
DR InParanoid; Q96KS0; -.
DR KO; K09592; -.
DR OMA; GGELWPL; -.
DR PhylomeDB; Q96KS0; -.
DR BioCyc; MetaCyc:ENSG00000171570-MONOMER; -.
DR BRENDA; 1.14.11.2; 2681.
DR Reactome; REACT_120956; Cellular responses to stress.
DR ChiTaRS; EGLN2; human.
DR GeneWiki; EGLN2; -.
DR GenomeRNAi; 112398; -.
DR NextBio; 78572; -.
DR PRO; PR:Q96KS0; -.
DR ArrayExpress; Q96KS0; -.
DR Bgee; Q96KS0; -.
DR CleanEx; HS_EGLN2; -.
DR Genevestigator; Q96KS0; -.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0008198; F:ferrous iron binding; NAS:UniProtKB.
DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0019826; F:oxygen sensor activity; IDA:UniProtKB.
DR GO; GO:0031545; F:peptidyl-proline 4-dioxygenase activity; IDA:FlyBase.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:UniProtKB.
DR GO; GO:0030520; P:intracellular estrogen receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:FlyBase.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:UniProtKB.
DR GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IMP:UniProtKB.
DR GO; GO:0061418; P:regulation of transcription from RNA polymerase II promoter in response to hypoxia; TAS:Reactome.
DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR InterPro; IPR006620; Pro_4_hyd_alph.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR SMART; SM00702; P4Hc; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; Complete proteome; Dioxygenase; Iron;
KW Metal-binding; Nucleus; Oxidoreductase; Reference proteome; Vitamin C.
FT CHAIN 1 407 Egl nine homolog 2.
FT /FTId=PRO_0000206664.
FT DOMAIN 278 376 Fe2OG dioxygenase.
FT REGION 89 134 Bipartite nuclear localization signal.
FT REGION 225 235 Beta(2)beta(3) 'finger-like' loop.
FT METAL 297 297 Iron (By similarity).
FT METAL 299 299 Iron (By similarity).
FT METAL 358 358 Iron (By similarity).
FT BINDING 367 367 2-oxoglutarate (By similarity).
FT VAR_SEQ 1 33 Missing (in isoform p40).
FT /FTId=VSP_038836.
FT MUTAGEN 1 1 M->A: Leads to expression of isoform p40
FT only.
FT MUTAGEN 34 34 M->A: Leads to expression of isoform p43
FT only.
FT MUTAGEN 102 102 K->A: Retained in the nucleus.
FT MUTAGEN 106 106 R->A: Retained in the nucleus.
FT MUTAGEN 113 113 R->A: Retained in the nucleus.
FT MUTAGEN 119 119 R->A: Cytoplasmic and nuclear
FT localization. Reduced transcriptional
FT activity of HIF1A as for wild type.
FT MUTAGEN 134 134 R->A: Retained in the nucleus.
FT MUTAGEN 297 297 H->A: Eliminates hydroxylase activity.
FT MUTAGEN 299 299 D->A: Eliminates hydroxylase activity.
FT MUTAGEN 358 358 H->A: Eliminates hydroxylase activity.
FT MUTAGEN 367 367 R->A: Eliminates hydroxylase activity.
FT MUTAGEN 367 367 R->K: Eliminates hydroxylase activity on
FT a HIF1A peptide.
FT CONFLICT 176 176 R -> P (in Ref. 2; AAK82943).
SQ SEQUENCE 407 AA; 43650 MW; F172E9B0482C9CF3 CRC64;
MDSPCQPQPL SQALPQLPGS SSEPLEPEPG RARMGVESYL PCPLLPSYHC PGVPSEASAG
SGTPRATATS TTASPLRDGF GGQDGGELRP LQSEGAAALV TKGCQRLAAQ GARPEAPKRK
WAEDGGDAPS PSKRPWARQE NQEAEREGGM SCSCSSGSGE ASAGLMEEAL PSAPERLALD
YIVPCMRYYG ICVKDSFLGA ALGGRVLAEV EALKRGGRLR DGQLVSQRAI PPRSIRGDQI
AWVEGHEPGC RSIGALMAHV DAVIRHCAGR LGSYVINGRT KAMVACYPGN GLGYVRHVDN
PHGDGRCITC IYYLNQNWDV KVHGGLLQIF PEGRPVVANI EPLFDRLLIF WSDRRNPHEV
KPAYATRYAI TVWYFDAKER AAAKDKYQLA SGQKGVQVPV SQPPTPT
//
ID EGLN2_HUMAN Reviewed; 407 AA.
AC Q96KS0; A8K5S0; Q8WWY4; Q9BV14;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Egl nine homolog 2;
DE EC=1.14.11.29;
DE AltName: Full=Estrogen-induced tag 6;
DE AltName: Full=HPH-3;
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 1;
DE Short=HIF-PH1;
DE Short=HIF-prolyl hydroxylase 1;
DE Short=HPH-1;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 1;
DE Short=PHD1;
GN Name=EGLN2; Synonyms=EIT6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P43).
RX PubMed=11574160; DOI=10.1016/S0378-1119(01)00633-3;
RA Taylor M.S.;
RT "Characterization and comparative analysis of the EGLN gene family.";
RL Gene 275:125-132(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P43), AND INDUCTION.
RC TISSUE=Mammary cancer;
RX PubMed=11850811; DOI=10.1038/sj.onc.1205113;
RA Seth P., Krop I., Porter D., Polyak K.;
RT "Novel estrogen and tamoxifen induced genes identified by SAGE (Serial
RT Analysis of Gene Expression).";
RL Oncogene 21:836-843(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Fetal brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Endometrium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P43).
RC TISSUE=Lung, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP REVIEW.
RX PubMed=11595178; DOI=10.1016/S0092-8674(01)00518-9;
RA Semenza G.L.;
RT "HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the
RT nucleus.";
RL Cell 107:1-3(2001).
RN [9]
RP FUNCTION, AND MUTAGENESIS OF HIS-358.
RX PubMed=11595184; DOI=10.1016/S0092-8674(01)00507-4;
RA Epstein A.C.R., Gleadle J.M., McNeill L.A., Hewitson K.S.,
RA O'Rourke J., Mole D.R., Mukherji M., Metzen E., Wilson M.I.,
RA Dhanda A., Tian Y.M., Masson N., Hamilton D.L., Jaakkola P.,
RA Barstead R., Hodgkin J., Maxwell P.H., Pugh C.W., Schofield C.J.,
RA Ratcliffe P.J.;
RT "C. elegans EGL-9 and mammalian homologs define a family of
RT dioxygenases that regulate HIF by prolyl hydroxylation.";
RL Cell 107:43-54(2001).
RN [10]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12163023; DOI=10.1016/S0006-291X(02)00862-8;
RA Oehme F., Ellinghaus P., Kolkhof P., Smith T.J., Ramakrishnan S.,
RA Huetter J., Schramm M., Flamme I.;
RT "Overexpression of PH-4, a novel putative proline 4-hydroxylase,
RT modulates activity of hypoxia-inducible transcription factors.";
RL Biochem. Biophys. Res. Commun. 296:343-349(2002).
RN [11]
RP MUTAGENESIS OF HIS-297; ASP-299; HIS-358 AND ARG-367.
RX PubMed=12039559; DOI=10.1016/S0960-894X(02)00219-6;
RA McNeill L.A., Hewitson K.S., Gleadle J.M., Horsfall L.E., Oldham N.J.,
RA Maxwell P.H., Pugh C.W., Ratcliffe P.J., Schofield C.J.;
RT "The use of dioxygen by HIF prolyl hydroxylase (PHD1).";
RL Bioorg. Med. Chem. Lett. 12:1547-1550(2002).
RN [12]
RP FUNCTION, AND SUBSTRATE RECOGNITION MOTIF.
RX PubMed=12181324; DOI=10.1074/jbc.M206955200;
RA Huang J., Zhao Q., Mooney S.M., Lee F.S.;
RT "Sequence determinants in hypoxia-inducible factor-1alpha for
RT hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3.";
RL J. Biol. Chem. 277:39792-39800(2002).
RN [13]
RP SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=12615973; DOI=10.1242/jcs.00318;
RA Metzen E., Berchner-Pfannschmidt U., Stengel P., Marxsen J.H.,
RA Stolze I., Klinger M., Huang W.Q., Wotzlaw C., Hellwig-Burgel T.,
RA Jelkmann W., Acker H., Fandrey J.;
RT "Intracellular localisation of human HIF-1 alpha hydroxylases:
RT implications for oxygen sensing.";
RL J. Cell Sci. 116:1319-1326(2003).
RN [14]
RP INDUCTION, AND SUBSTRATE SPECIFICITY.
RX PubMed=15247232; DOI=10.1074/jbc.M406026200;
RA Appelhoff R.J., Tian Y.M., Raval R.R., Turley H., Harris A.L.,
RA Pugh C.W., Ratcliffe P.J., Gleadle J.M.;
RT "Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3
RT in the regulation of hypoxia-inducible factor.";
RL J. Biol. Chem. 279:38458-38465(2004).
RN [15]
RP FUNCTION, INTERACTION WITH SIAH2, ALTERNATIVE INITIATION, INDUCTION,
RP AND MUTAGENESIS OF MET-1 AND MET-34.
RX PubMed=16509823; DOI=10.1042/BJ20051996;
RA Tian Y.M., Mole D.R., Ratcliffe P.J., Gleadle J.M.;
RT "Characterization of different isoforms of the HIF prolyl hydroxylase
RT PHD1 generated by alternative initiation.";
RL Biochem. J. 397:179-186(2006).
RN [16]
RP FUNCTION.
RX PubMed=17114296; DOI=10.1073/pnas.0602235103;
RA Cummins E.P., Berra E., Comerford K.M., Ginouves A., Fitzgerald K.T.,
RA Seeballuck F., Godson C., Nielsen J.E., Moynagh P., Pouyssegur J.,
RA Taylor C.T.;
RT "Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving
RT insight into hypoxia-induced NFkappaB activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18154-18159(2006).
RN [17]
RP SUBCELLULAR LOCATION.
RX PubMed=19631610; DOI=10.1016/j.bbrc.2009.07.090;
RA Steinhoff A., Pientka F.K., Mockel S., Kettelhake A., Hartmann E.,
RA Kohler M., Depping R.;
RT "Cellular oxygen sensing: Importins and exportins are mediators of
RT intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2.";
RL Biochem. Biophys. Res. Commun. 387:705-711(2009).
RN [18]
RP SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS OF LYS-102; ARG-106;
RP ARG-113; ARG-119 AND ARG-134.
RX PubMed=19339211; DOI=10.1016/j.bbamcr.2009.01.014;
RA Yasumoto K., Kowata Y., Yoshida A., Torii S., Sogawa K.;
RT "Role of the intracellular localization of HIF-prolyl hydroxylases.";
RL Biochim. Biophys. Acta 1793:792-797(2009).
RN [19]
RP SUBSTRATE SPECIFICITY, AND MASS SPECTROMETRY.
RX PubMed=21410436; DOI=10.1042/BJ20101201;
RA Pappalardi M.B., McNulty D.E., Martin J.D., Fisher K.E., Jiang Y.,
RA Burns M.C., Zhao H., Ho T., Sweitzer S., Schwartz B., Annan R.S.,
RA Copeland R.A., Tummino P.J., Luo L.;
RT "Biochemical characterization of human HIF hydroxylases using HIF
RT protein substrates that contain all three hydroxylation sites.";
RL Biochem. J. 436:363-369(2011).
RN [20]
RP INTERACTION WITH LIMD1; WTIP AND AJUBA.
RX PubMed=22286099; DOI=10.1038/ncb2424;
RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C.,
RA Feng Y., Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J.,
RA Ingvarsson S., Ratcliffe P.J., Longmore G.D., Sharp T.V.;
RT "The LIMD1 protein bridges an association between the prolyl
RT hydroxylases and VHL to repress HIF-1 activity.";
RL Nat. Cell Biol. 14:201-208(2012).
RN [21]
RP FUNCTION.
RX PubMed=23932902; DOI=10.1016/j.devcel.2013.06.014;
RA Moser S.C., Bensaddek D., Ortmann B., Maure J.F., Mudie S., Blow J.J.,
RA Lamond A.I., Swedlow J.R., Rocha S.;
RT "PHD1 links cell-cycle progression to oxygen sensing through
RT hydroxylation of the centrosomal protein Cep192.";
RL Dev. Cell 26:381-392(2013).
CC -!- FUNCTION: Cellular oxygen sensor that catalyzes, under normoxic
CC conditions, the post-translational formation of 4-hydroxyproline
CC in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a
CC specific proline found in each of the oxygen-dependent degradation
CC (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A.
CC Also hydroxylates HIF2A. Has a preference for the CODD site for
CC both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for
CC proteasomal degradation via the von Hippel-Lindau ubiquitination
CC complex. Under hypoxic conditions, the hydroxylation reaction is
CC attenuated allowing HIFs to escape degradation resulting in their
CC translocation to the nucleus, heterodimerization with HIF1B, and
CC increased expression of hypoxy-inducible genes. EGLN2 is involved
CC in regulating hypoxia tolerance and apoptosis in cardiac and
CC skeletal muscle. Also regulates susceptibility to normoxic
CC oxidative neuronal death. Links oxygen sensing to cell cycle and
CC primary cilia formation by hydroxylating the critical centrosome
CC component CEP192 which promotes its ubiquitination and subsequent
CC proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB
CC activation in hypoxic conditions. Target proteins are
CC preferencially recognized via a LXXLAP motif.
CC -!- CATALYTIC ACTIVITY: Hypoxia-inducible factor-L-proline + 2-
CC oxoglutarate + O(2) = hypoxia-inducible factor-trans-4-hydroxy-L-
CC proline + succinate + CO(2).
CC -!- COFACTOR: Binds 1 Fe(2+) ion per subunit.
CC -!- COFACTOR: Ascorbate.
CC -!- SUBUNIT: Interacts (preferably isoform p40) with SIAH2; the
CC interaction targets both SIAH2 isoforms for proteasomal
CC degradation in vitro. Interacts with LIMD1, WTIP and AJUBA.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=p43; Synonyms=PHD1p43;
CC IsoId=Q96KS0-1; Sequence=Displayed;
CC Name=p40; Synonyms=PHD1p40;
CC IsoId=Q96KS0-2; Sequence=VSP_038836;
CC -!- TISSUE SPECIFICITY: Expressed in adult and fetal heart, brain,
CC liver, lung, skeletal muscle, and kidney. Also expressed in testis
CC and placenta. Highest levels in adult brain, placenta, lung,
CC kidney, and testis. Expressed in hormone responsive tissues,
CC including normal and cancerous mammary, ovarian and prostate
CC epithelium.
CC -!- INDUCTION: By estrogen. Isoform p43 is induced by hypoxia leading
CC to protein stability. Isoform p40 repressed by hypoxia. Both
CC isoforms are induced by proteasomal inhibitor MG132 (at protein
CC level).
CC -!- DOMAIN: The Beta(2)beta(3) 'finger-like' loop domain is important
CC for substrate (HIFs' CODD/NODD) selectivity (By similarity).
CC -!- SIMILARITY: Contains 1 Fe2OG dioxygenase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH01723.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; AJ310544; CAC42510.1; -; mRNA.
DR EMBL; AY040565; AAK82943.1; -; mRNA.
DR EMBL; AK291385; BAF84074.1; -; mRNA.
DR EMBL; AL832506; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC008537; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471126; EAW57008.1; -; Genomic_DNA.
DR EMBL; BC001723; AAH01723.1; ALT_INIT; mRNA.
DR EMBL; BC036051; AAH36051.1; -; mRNA.
DR RefSeq; NP_444274.1; NM_053046.3.
DR RefSeq; NP_542770.2; NM_080732.3.
DR RefSeq; XP_005258526.1; XM_005258469.1.
DR RefSeq; XP_005258527.1; XM_005258470.1.
DR RefSeq; XP_005258528.1; XM_005258471.1.
DR UniGene; Hs.515417; -.
DR UniGene; Hs.631539; -.
DR UniGene; Hs.730737; -.
DR ProteinModelPortal; Q96KS0; -.
DR SMR; Q96KS0; 176-387.
DR IntAct; Q96KS0; 5.
DR MINT; MINT-1186497; -.
DR STRING; 9606.ENSP00000307080; -.
DR BindingDB; Q96KS0; -.
DR ChEMBL; CHEMBL3028; -.
DR DrugBank; DB00126; Vitamin C.
DR PhosphoSite; Q96KS0; -.
DR DMDM; 32129513; -.
DR PaxDb; Q96KS0; -.
DR PRIDE; Q96KS0; -.
DR DNASU; 112398; -.
DR Ensembl; ENST00000303961; ENSP00000307080; ENSG00000269858.
DR Ensembl; ENST00000406058; ENSP00000385253; ENSG00000269858.
DR Ensembl; ENST00000593726; ENSP00000469686; ENSG00000269858.
DR Ensembl; ENST00000594140; ENSP00000472414; ENSG00000269858.
DR GeneID; 112398; -.
DR KEGG; hsa:112398; -.
DR UCSC; uc002opg.4; human.
DR CTD; 112398; -.
DR GeneCards; GC19P041304; -.
DR HGNC; HGNC:14660; EGLN2.
DR MIM; 606424; gene.
DR neXtProt; NX_Q96KS0; -.
DR PharmGKB; PA27671; -.
DR eggNOG; COG3751; -.
DR HOGENOM; HOG000013099; -.
DR HOVERGEN; HBG051456; -.
DR InParanoid; Q96KS0; -.
DR KO; K09592; -.
DR OMA; GGELWPL; -.
DR PhylomeDB; Q96KS0; -.
DR BioCyc; MetaCyc:ENSG00000171570-MONOMER; -.
DR BRENDA; 1.14.11.2; 2681.
DR Reactome; REACT_120956; Cellular responses to stress.
DR ChiTaRS; EGLN2; human.
DR GeneWiki; EGLN2; -.
DR GenomeRNAi; 112398; -.
DR NextBio; 78572; -.
DR PRO; PR:Q96KS0; -.
DR ArrayExpress; Q96KS0; -.
DR Bgee; Q96KS0; -.
DR CleanEx; HS_EGLN2; -.
DR Genevestigator; Q96KS0; -.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0008198; F:ferrous iron binding; NAS:UniProtKB.
DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0019826; F:oxygen sensor activity; IDA:UniProtKB.
DR GO; GO:0031545; F:peptidyl-proline 4-dioxygenase activity; IDA:FlyBase.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:UniProtKB.
DR GO; GO:0030520; P:intracellular estrogen receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:FlyBase.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:UniProtKB.
DR GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IMP:UniProtKB.
DR GO; GO:0061418; P:regulation of transcription from RNA polymerase II promoter in response to hypoxia; TAS:Reactome.
DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR InterPro; IPR006620; Pro_4_hyd_alph.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR SMART; SM00702; P4Hc; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; Complete proteome; Dioxygenase; Iron;
KW Metal-binding; Nucleus; Oxidoreductase; Reference proteome; Vitamin C.
FT CHAIN 1 407 Egl nine homolog 2.
FT /FTId=PRO_0000206664.
FT DOMAIN 278 376 Fe2OG dioxygenase.
FT REGION 89 134 Bipartite nuclear localization signal.
FT REGION 225 235 Beta(2)beta(3) 'finger-like' loop.
FT METAL 297 297 Iron (By similarity).
FT METAL 299 299 Iron (By similarity).
FT METAL 358 358 Iron (By similarity).
FT BINDING 367 367 2-oxoglutarate (By similarity).
FT VAR_SEQ 1 33 Missing (in isoform p40).
FT /FTId=VSP_038836.
FT MUTAGEN 1 1 M->A: Leads to expression of isoform p40
FT only.
FT MUTAGEN 34 34 M->A: Leads to expression of isoform p43
FT only.
FT MUTAGEN 102 102 K->A: Retained in the nucleus.
FT MUTAGEN 106 106 R->A: Retained in the nucleus.
FT MUTAGEN 113 113 R->A: Retained in the nucleus.
FT MUTAGEN 119 119 R->A: Cytoplasmic and nuclear
FT localization. Reduced transcriptional
FT activity of HIF1A as for wild type.
FT MUTAGEN 134 134 R->A: Retained in the nucleus.
FT MUTAGEN 297 297 H->A: Eliminates hydroxylase activity.
FT MUTAGEN 299 299 D->A: Eliminates hydroxylase activity.
FT MUTAGEN 358 358 H->A: Eliminates hydroxylase activity.
FT MUTAGEN 367 367 R->A: Eliminates hydroxylase activity.
FT MUTAGEN 367 367 R->K: Eliminates hydroxylase activity on
FT a HIF1A peptide.
FT CONFLICT 176 176 R -> P (in Ref. 2; AAK82943).
SQ SEQUENCE 407 AA; 43650 MW; F172E9B0482C9CF3 CRC64;
MDSPCQPQPL SQALPQLPGS SSEPLEPEPG RARMGVESYL PCPLLPSYHC PGVPSEASAG
SGTPRATATS TTASPLRDGF GGQDGGELRP LQSEGAAALV TKGCQRLAAQ GARPEAPKRK
WAEDGGDAPS PSKRPWARQE NQEAEREGGM SCSCSSGSGE ASAGLMEEAL PSAPERLALD
YIVPCMRYYG ICVKDSFLGA ALGGRVLAEV EALKRGGRLR DGQLVSQRAI PPRSIRGDQI
AWVEGHEPGC RSIGALMAHV DAVIRHCAGR LGSYVINGRT KAMVACYPGN GLGYVRHVDN
PHGDGRCITC IYYLNQNWDV KVHGGLLQIF PEGRPVVANI EPLFDRLLIF WSDRRNPHEV
KPAYATRYAI TVWYFDAKER AAAKDKYQLA SGQKGVQVPV SQPPTPT
//
MIM
606424
*RECORD*
*FIELD* NO
606424
*FIELD* TI
*606424 EGL9, C. ELEGANS, HOMOLOG OF, 2; EGLN2
;;PROLYL HYDROXYLASE DOMAIN-CONTAINING PROTEIN 1; PHD1;;
read moreHYPOXIA-INDUCIBLE FACTOR PROLYL 4-HYDROXYLASE 1; HIFPH1; HIFP4H1;;
HIF PROLYL 4-HYDROXYLASE 1
*FIELD* TX
CLONING
HIF is a transcriptional complex that plays a central role in mammalian
oxygen homeostasis. Posttranslational modification by prolyl
hydroxylation is a key regulatory event that targets HIF-alpha (HIF1;
603348) subunits for proteasomal destruction via the von Hippel-Lindau
(VHL; 608537) ubiquitylation complex. Epstein et al. (2001) defined a
conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans and
identified Egl9 as a dioxygenase that regulates HIF by prolyl
hydroxylation. In mammalian cells, they showed that the HIF-prolyl
hydroxylases are represented by 3 proteins with a conserved
2-histidine-1-carboxylate iron coordination motif at the catalytic site.
The genes encoding these proteins were cloned and termed PHD1, PHD2
(606425), and PHD3 (606426) by the authors. Direct modulation of
recombinant enzyme activity by graded hypoxia, iron chelation, and
cobaltous ions mirrored the characteristics of HIF induction in vivo,
fulfilling requirements for these enzymes being oxygen sensors that
regulate HIF.
Bruick and McKnight (2001) independently identified the conserved family
of HIF prolyl hydroxylase enzymes, which they called HPH1, 2, and 3,
respectively, that appear to be responsible for the posttranslational
modification of HIF that targets it for ubiquitination.
By quantitative RT-PCR, Oehme et al. (2002) found highest EGLN2
expression in testis, with much lower expression in the 16 other human
tissues examined.
Independently, Hirsila et al. (2003) cloned HIFP4H1, HIFP4H2, and
HIFP4HD3 by PCR of human colon, aorta, and lung cDNA. The deduced
407-amino acid HIFP4H1 protein contains a C-terminal catalytic domain
with motifs for binding iron and the C5 carboxyl group of
2-oxoglutarate. PCR analysis of adult and fetal samples revealed HIFP4H1
expression in all tissues examined, with highest expression in adult
brain, placenta, lung, and kidney.
GENE FUNCTION
In cultured mammalian cells, Bruick and McKnight (2001) found that the
inappropriate accumulation of HIF caused by forced expression of the
HIF1-alpha subunit under normoxic conditions was attenuated by
coexpression of HPH. Suppression of HPH in cultured Drosophila
melanogaster cells by RNA interference resulted in elevated expression
of the hypoxia-inducible gene LDH (see 150000) under normoxic
conditions. Bruick and McKnight (2001) concluded that HPH is an
essential component of the pathway through which cells sense oxygen.
Using recombinant proteins expressed in insect cells, Hirsila et al.
(2003) found that HIFP4H1, HIFP4H2, and HIFP4H3 showed in vitro
2-oxoglutarate-dependent hydroxylation of a 19-residue peptide
corresponding to the C-terminal prolyl hydroxylation site of HIF1-alpha.
All 3 enzymes showed lower or no activity against a peptide
corresponding to a more N-terminal putative prolyl hydroxylation site in
HIF1-alpha. All 3 enzymes hydroxylated peptides designed from putative
prolyl hydroxylation sites of human HIF2-alpha (EPAS1; 603349),
HIF3-alpha (HIF3A; 609976), and C. elegans HIF-alpha.
Nakayama et al. (2004) demonstrated that PHD1 and PHD3 abundance is
regulated via their targeting for proteasome-dependent degradation by
the E3 ubiquitin ligases SIAH1 (602212) and SIAH2 (602213) under hypoxia
conditions. Siah2-null mouse fibroblasts exhibited prolonged Phd3
half-life, resulting in lower levels of Hif1a expression during hypoxia.
Hypoxia-induced Hif1a expression was completely inhibited in
Siah1a/Siah2-null cells, yet could be rescued upon inhibition of Phd3 by
RNA interference. In 293T cells, SIAH2 targeting of PHD3 for degradation
increased upon exposure to even mild hypoxic conditions, which coincided
with increased SIAH2 transcription. Siah2-null mice subjected to hypoxia
displayed an impaired hyperpneic respiratory response and reduced levels
of hemoglobin. Nakayama et al. (2004) concluded that control of PHD1 and
PHD3 by SIAH1 and SIAH2 constitutes another level of complexity in the
regulation of HIF1A during hypoxia.
Minamishima and Kaelin (2010) showed that loss of all 3 PHDs (PHD1;
PHD2, 606425; and PHD3, 606426) in the liver dramatically increased EPO
(133170) and hematocrit values to concentrations vastly in excess of
those achieved after renal PHD2 inactivation. Minamishima and Kaelin
(2010) found that PHD2 inactivation is sufficient to induce near maximal
renal EPO production, whereas inactivation of all 3 PHDs is needed to
reactivate hepatic EPO production.
ANIMAL MODEL
HIF prolyl hydroxylases are oxygen sensors that regulate the stability
of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner.
Aragones et al. (2008) showed that loss of Phd1 expression in knockout
mice lowers oxygen consumption in skeletal muscle by reprogramming
glucose metabolism from oxidative to more anaerobic ATP production
through activation of a PPAR-alpha (170998) pathway. This metabolic
adaptation to oxygen conservation impairs oxidative muscle performance
in healthy conditions, but it provides acute protection of myofibers
against lethal ischemia. Hypoxia tolerance is due to reduced generation
of oxidative stress, which allows Phd1-deficient myofibers to preserve
mitochondrial respiration. Of medical importance, conditional knockdown
of Phd1 also rapidly induces hypoxia tolerance. These findings delineate
a new role of Phd1 in hypoxia tolerance and offer new treatment
perspectives for disorders characterized by oxidative stress.
MAPPING
Hartz (2012) mapped the EGLN2 gene to chromosome 19q13.2 based on an
alignment of the EGLN2 sequence (GenBank GENBANK AJ310544) with the
genomic sequence (GRCh37).
*FIELD* RF
1. Aragones, J.; Schneider, M.; Van Geyte, K.; Fraisl, P.; Dresselaers,
T.; Mazzone, M.; Dirkx, R.; Zacchigna, S.; Lemieux, H.; Jeoung, N.
H.; Lambrechts, D.; Bishop, T.; and 35 others: Deficiency or inhibition
of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal
metabolism. Nature Genet. 40: 170-180, 2008.
2. Bruick, R. K.; McKnight, S. L.: A conserved family of prolyl-4-hydroxylases
that modify HIF. Science 294: 1337-1340, 2001.
3. Epstein, A. C. R.; Gleadle, J. M.; McNeill, L. A.; Hewitson, K.
S.; O'Rourke, J.; Mole, D. R.; Mukherji, M.; Metzen, E.; Wilson, M.
I.; Dhanda, A.; Tian, Y.-M.; Masson, N.; Hamilton, D. L.; Jaakkola,
P.; Barstead, R.; Hodgkin, J.; Maxwell, P. H.; Pugh, C. W.; Schofield,
C. J.; Ratcliffe, P. J.: C. elegans EGL-9 and mammalian homologs
define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:
43-54, 2001.
4. Hartz, P. A.: Personal Communication. Baltimore, Md. 4/19/2012.
5. Hirsila, M.; Koivunen, P.; Gunzler, V.; Kivirikko, K. I.; Myllyharju,
J.: Characterization of the human propyl 4-hydroxylases that modify
the hypoxia-inducible factor. J. Biol. Chem. 278: 30772-30780, 2003.
6. Minamishima, Y. A.; Kaelin, W. G., Jr.: Reactivation of hepatic
EPO synthesis in mice after PHD loss. Science 329: 407 only, 2010.
7. Nakayama, K.; Frew, I. J.; Hagensen, M.; Skals, M.; Habelhah, H.;
Bhoumik, A.; Kadoya, T.; Erdjument-Bromage, H.; Tempst, P.; Frappell,
P. B.; Bowtell, D. D.; Ronai, Z.: Siah2 regulates stability of prolyl-hydroxylases,
controls HIF1-alpha abundance, and modulates physiologic responses
to hypoxia. Cell 117: 941-952, 2004.
8. Oehme, F.; Ellinghaus, P.; Kolkhof, P.; Smith, T. J.; Ramakrishnan,
S.; Hutter, J.; Schramm, M.; Flamme, I.: Overexpression of PH-4,
a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible
transcription factors. Biochem. Biophys. Res. Commun. 296: 343-349,
2002.
*FIELD* CN
Ada Hamosh - updated: 4/19/2012
Ada Hamosh - updated: 9/1/2010
Victor A. McKusick - updated: 3/10/2008
Stylianos E. Antonarakis - updated: 8/4/2004
Ada Hamosh - updated: 11/30/2001
*FIELD* CD
Stylianos E. Antonarakis: 10/31/2001
*FIELD* ED
mgross: 04/20/2012
terry: 4/19/2012
alopez: 9/1/2010
terry: 9/1/2010
alopez: 3/13/2008
terry: 3/10/2008
terry: 4/6/2005
mgross: 8/4/2004
ckniffin: 3/23/2004
alopez: 12/3/2001
terry: 11/30/2001
mgross: 10/31/2001
*RECORD*
*FIELD* NO
606424
*FIELD* TI
*606424 EGL9, C. ELEGANS, HOMOLOG OF, 2; EGLN2
;;PROLYL HYDROXYLASE DOMAIN-CONTAINING PROTEIN 1; PHD1;;
read moreHYPOXIA-INDUCIBLE FACTOR PROLYL 4-HYDROXYLASE 1; HIFPH1; HIFP4H1;;
HIF PROLYL 4-HYDROXYLASE 1
*FIELD* TX
CLONING
HIF is a transcriptional complex that plays a central role in mammalian
oxygen homeostasis. Posttranslational modification by prolyl
hydroxylation is a key regulatory event that targets HIF-alpha (HIF1;
603348) subunits for proteasomal destruction via the von Hippel-Lindau
(VHL; 608537) ubiquitylation complex. Epstein et al. (2001) defined a
conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans and
identified Egl9 as a dioxygenase that regulates HIF by prolyl
hydroxylation. In mammalian cells, they showed that the HIF-prolyl
hydroxylases are represented by 3 proteins with a conserved
2-histidine-1-carboxylate iron coordination motif at the catalytic site.
The genes encoding these proteins were cloned and termed PHD1, PHD2
(606425), and PHD3 (606426) by the authors. Direct modulation of
recombinant enzyme activity by graded hypoxia, iron chelation, and
cobaltous ions mirrored the characteristics of HIF induction in vivo,
fulfilling requirements for these enzymes being oxygen sensors that
regulate HIF.
Bruick and McKnight (2001) independently identified the conserved family
of HIF prolyl hydroxylase enzymes, which they called HPH1, 2, and 3,
respectively, that appear to be responsible for the posttranslational
modification of HIF that targets it for ubiquitination.
By quantitative RT-PCR, Oehme et al. (2002) found highest EGLN2
expression in testis, with much lower expression in the 16 other human
tissues examined.
Independently, Hirsila et al. (2003) cloned HIFP4H1, HIFP4H2, and
HIFP4HD3 by PCR of human colon, aorta, and lung cDNA. The deduced
407-amino acid HIFP4H1 protein contains a C-terminal catalytic domain
with motifs for binding iron and the C5 carboxyl group of
2-oxoglutarate. PCR analysis of adult and fetal samples revealed HIFP4H1
expression in all tissues examined, with highest expression in adult
brain, placenta, lung, and kidney.
GENE FUNCTION
In cultured mammalian cells, Bruick and McKnight (2001) found that the
inappropriate accumulation of HIF caused by forced expression of the
HIF1-alpha subunit under normoxic conditions was attenuated by
coexpression of HPH. Suppression of HPH in cultured Drosophila
melanogaster cells by RNA interference resulted in elevated expression
of the hypoxia-inducible gene LDH (see 150000) under normoxic
conditions. Bruick and McKnight (2001) concluded that HPH is an
essential component of the pathway through which cells sense oxygen.
Using recombinant proteins expressed in insect cells, Hirsila et al.
(2003) found that HIFP4H1, HIFP4H2, and HIFP4H3 showed in vitro
2-oxoglutarate-dependent hydroxylation of a 19-residue peptide
corresponding to the C-terminal prolyl hydroxylation site of HIF1-alpha.
All 3 enzymes showed lower or no activity against a peptide
corresponding to a more N-terminal putative prolyl hydroxylation site in
HIF1-alpha. All 3 enzymes hydroxylated peptides designed from putative
prolyl hydroxylation sites of human HIF2-alpha (EPAS1; 603349),
HIF3-alpha (HIF3A; 609976), and C. elegans HIF-alpha.
Nakayama et al. (2004) demonstrated that PHD1 and PHD3 abundance is
regulated via their targeting for proteasome-dependent degradation by
the E3 ubiquitin ligases SIAH1 (602212) and SIAH2 (602213) under hypoxia
conditions. Siah2-null mouse fibroblasts exhibited prolonged Phd3
half-life, resulting in lower levels of Hif1a expression during hypoxia.
Hypoxia-induced Hif1a expression was completely inhibited in
Siah1a/Siah2-null cells, yet could be rescued upon inhibition of Phd3 by
RNA interference. In 293T cells, SIAH2 targeting of PHD3 for degradation
increased upon exposure to even mild hypoxic conditions, which coincided
with increased SIAH2 transcription. Siah2-null mice subjected to hypoxia
displayed an impaired hyperpneic respiratory response and reduced levels
of hemoglobin. Nakayama et al. (2004) concluded that control of PHD1 and
PHD3 by SIAH1 and SIAH2 constitutes another level of complexity in the
regulation of HIF1A during hypoxia.
Minamishima and Kaelin (2010) showed that loss of all 3 PHDs (PHD1;
PHD2, 606425; and PHD3, 606426) in the liver dramatically increased EPO
(133170) and hematocrit values to concentrations vastly in excess of
those achieved after renal PHD2 inactivation. Minamishima and Kaelin
(2010) found that PHD2 inactivation is sufficient to induce near maximal
renal EPO production, whereas inactivation of all 3 PHDs is needed to
reactivate hepatic EPO production.
ANIMAL MODEL
HIF prolyl hydroxylases are oxygen sensors that regulate the stability
of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner.
Aragones et al. (2008) showed that loss of Phd1 expression in knockout
mice lowers oxygen consumption in skeletal muscle by reprogramming
glucose metabolism from oxidative to more anaerobic ATP production
through activation of a PPAR-alpha (170998) pathway. This metabolic
adaptation to oxygen conservation impairs oxidative muscle performance
in healthy conditions, but it provides acute protection of myofibers
against lethal ischemia. Hypoxia tolerance is due to reduced generation
of oxidative stress, which allows Phd1-deficient myofibers to preserve
mitochondrial respiration. Of medical importance, conditional knockdown
of Phd1 also rapidly induces hypoxia tolerance. These findings delineate
a new role of Phd1 in hypoxia tolerance and offer new treatment
perspectives for disorders characterized by oxidative stress.
MAPPING
Hartz (2012) mapped the EGLN2 gene to chromosome 19q13.2 based on an
alignment of the EGLN2 sequence (GenBank GENBANK AJ310544) with the
genomic sequence (GRCh37).
*FIELD* RF
1. Aragones, J.; Schneider, M.; Van Geyte, K.; Fraisl, P.; Dresselaers,
T.; Mazzone, M.; Dirkx, R.; Zacchigna, S.; Lemieux, H.; Jeoung, N.
H.; Lambrechts, D.; Bishop, T.; and 35 others: Deficiency or inhibition
of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal
metabolism. Nature Genet. 40: 170-180, 2008.
2. Bruick, R. K.; McKnight, S. L.: A conserved family of prolyl-4-hydroxylases
that modify HIF. Science 294: 1337-1340, 2001.
3. Epstein, A. C. R.; Gleadle, J. M.; McNeill, L. A.; Hewitson, K.
S.; O'Rourke, J.; Mole, D. R.; Mukherji, M.; Metzen, E.; Wilson, M.
I.; Dhanda, A.; Tian, Y.-M.; Masson, N.; Hamilton, D. L.; Jaakkola,
P.; Barstead, R.; Hodgkin, J.; Maxwell, P. H.; Pugh, C. W.; Schofield,
C. J.; Ratcliffe, P. J.: C. elegans EGL-9 and mammalian homologs
define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:
43-54, 2001.
4. Hartz, P. A.: Personal Communication. Baltimore, Md. 4/19/2012.
5. Hirsila, M.; Koivunen, P.; Gunzler, V.; Kivirikko, K. I.; Myllyharju,
J.: Characterization of the human propyl 4-hydroxylases that modify
the hypoxia-inducible factor. J. Biol. Chem. 278: 30772-30780, 2003.
6. Minamishima, Y. A.; Kaelin, W. G., Jr.: Reactivation of hepatic
EPO synthesis in mice after PHD loss. Science 329: 407 only, 2010.
7. Nakayama, K.; Frew, I. J.; Hagensen, M.; Skals, M.; Habelhah, H.;
Bhoumik, A.; Kadoya, T.; Erdjument-Bromage, H.; Tempst, P.; Frappell,
P. B.; Bowtell, D. D.; Ronai, Z.: Siah2 regulates stability of prolyl-hydroxylases,
controls HIF1-alpha abundance, and modulates physiologic responses
to hypoxia. Cell 117: 941-952, 2004.
8. Oehme, F.; Ellinghaus, P.; Kolkhof, P.; Smith, T. J.; Ramakrishnan,
S.; Hutter, J.; Schramm, M.; Flamme, I.: Overexpression of PH-4,
a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible
transcription factors. Biochem. Biophys. Res. Commun. 296: 343-349,
2002.
*FIELD* CN
Ada Hamosh - updated: 4/19/2012
Ada Hamosh - updated: 9/1/2010
Victor A. McKusick - updated: 3/10/2008
Stylianos E. Antonarakis - updated: 8/4/2004
Ada Hamosh - updated: 11/30/2001
*FIELD* CD
Stylianos E. Antonarakis: 10/31/2001
*FIELD* ED
mgross: 04/20/2012
terry: 4/19/2012
alopez: 9/1/2010
terry: 9/1/2010
alopez: 3/13/2008
terry: 3/10/2008
terry: 4/6/2005
mgross: 8/4/2004
ckniffin: 3/23/2004
alopez: 12/3/2001
terry: 11/30/2001
mgross: 10/31/2001