EGLN1 (egl nine homolog 1 (C. elegans))

2008-01-01   Terhi Jokilehto , Panu M Jaakkola 

Hypoxia group, Turku centre for Biotechnology, Tykistokatu 6, 20520 Turku, Finland

Identity

HGNC
LOCATION
1q42.2
LOCUSID
ALIAS
C1orf12,ECYT3,HALAH,HIF-PH2,HIFPH2,HPH-2,HPH2,PHD2,SM20,ZMYND6
FUSION GENES

DNA/RNA

Description

EGLN1 gene is located on chromosome 1, location 229568054-229627413. Gene spans 61293 bases and has 5 exons.

Transcription

PHD2 expression is strongly induced in hypoxia by the HIF-1α transcription factor. Primary transcript length is 5936 bases. On mRNA level two splice variants have been proposed, lacking exons 3 or 4, but these have not been confirmed on protein level.

Proteins

Description

PHD2 protein is 426 amino acids long and approximately 46 kDa. It has a zf-MYND domain (aa 21-58) and a 2-OG-FeII-oxygenase domain (aa205-391).

Expression

Ubiquitous.

Localisation

Predominantly cytoplasmic.

Function

PHD2 is a member of the 2-oxoglutarate-dependent, non-haem iron binding dioxygenases.
PHD2 post-translationally regulates the levels of hypoxia-inducible factor-α (HIF-α) subunits in normoxic conditions by hydroxylating them in an oxygen-dependant manner on specific proline residues. This enables recognition of HIF by the VHL ubiquitin ligase complex and subsequent degradation of HIF by the proteasome. In hypoxic conditions the hydroxylation is significantly decreased, and the HIF-α subunits are stabilized. PHD2 is considered the main HIF-1α regulator in normoxic and mildly hypoxic conditions.

Homology

EGLN1 has two paralogs: EGLN2 and EGLN3 Homologs have been found in all multicellular organisms investigated.

Mutations

Note

Homozygous deletion confers embryonic lethality in mouse.

Germinal

Heterozygous mutations have been associated with familial erythrocytosis. Currently three point mutations: G1112A ->Arg371His, C950G -> Pro317Arg, C1129T-> Gln377X, one deletion: 606delG -> frameshift, and one insertion: 840_841insA -> frameshift have been reported.

Implicated in

Entity name
Head and neck squamous cell carcinoma
Note
Increased expression levels and nuclear translocation have been associated with the aggressiveness of the carcinoma.

Bibliography

Pubmed IDLast YearTitleAuthors
179335622008Disturbance in the HIF-1alpha pathway associated with erythrocytosis: further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene.Al-Sheikh M et al
152472322004Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor.Appelhoff RJ et al
129129072003HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia.Berra E et al
110560532000Mapping, characterization, and expression analysis of the SM-20 human homologue, c1orf12, and identification of a novel related gene, SCAND2.Dupuy D et al
115951842001C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.Epstein AC et al
127889212003Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor.Hirsilä M et al
112928622001HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.Ivan M et al
112928612001Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.Jaakkola P et al
164890602006Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness.Jokilehto T et al
126159732003Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing.Metzen E et al
155632752005Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element.Metzen E et al
175791852007A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove.Percy MJ et al
164071302006A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis.Percy MJ et al
169663702006Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2.Takeda K et al
115741602001Characterization and comparative analysis of the EGLN gene family.Taylor MS et al

Other Information

Locus ID:

NCBI: 54583
MIM: 606425
HGNC: 1232
Ensembl: ENSG00000135766

Variants:

dbSNP: 54583
ClinVar: 54583
TCGA: ENSG00000135766
COSMIC: EGLN1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000135766ENST00000366641Q9GZT9
ENSG00000135766ENST00000366641R4SCQ0
ENSG00000135766ENST00000654803A0A590UJT7
ENSG00000135766ENST00000658954A0A590UJ78
ENSG00000135766ENST00000667629A0A590UJZ0
ENSG00000135766ENST00000670301A0A590UJD6

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Renal cell carcinomaKEGGko05211
Pathways in cancerKEGGhsa05200
Renal cell carcinomaKEGGhsa05211
HIF-1 signaling pathwayKEGGhsa04066
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to hypoxiaREACTOMER-HSA-2262749
Regulation of Hypoxia-inducible Factor (HIF) by oxygenREACTOMER-HSA-1234174
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor AlphaREACTOMER-HSA-1234176

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
212516132011Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.828
129129072003HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia.393
204668842010Genetic evidence for high-altitude adaptation in Tibet.354
152472322004Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor.329
223438962012Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.276
210304262011Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas.119
209619602011A genome-wide search for signals of high-altitude adaptation in Tibetans.114
168158402006Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression.104
164071302006A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis.100
167828142006Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).98

Citation

Terhi Jokilehto ; Panu M Jaakkola

EGLN1 (egl nine homolog 1 (C. elegans))

Atlas Genet Cytogenet Oncol Haematol. 2008-01-01

Online version: http://atlasgeneticsoncology.org/gene/44140/egln1