EGLN1 (egl nine homolog 1 (C. elegans))
2008-01-01 Terhi Jokilehto , Panu M Jaakkola AffiliationHypoxia 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.
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 17933562 | 2008 | Disturbance 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 |
| 15247232 | 2004 | Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. | Appelhoff RJ et al |
| 12912907 | 2003 | HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. | Berra E et al |
| 11056053 | 2000 | Mapping, characterization, and expression analysis of the SM-20 human homologue, c1orf12, and identification of a novel related gene, SCAND2. | Dupuy D et al |
| 11595184 | 2001 | C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. | Epstein AC et al |
| 12788921 | 2003 | Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. | Hirsilä M et al |
| 11292862 | 2001 | HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. | Ivan M et al |
| 11292861 | 2001 | Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. | Jaakkola P et al |
| 16489060 | 2006 | Overexpression 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 |
| 12615973 | 2003 | Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. | Metzen E et al |
| 15563275 | 2005 | Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element. | Metzen E et al |
| 17579185 | 2007 | A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. | Percy MJ et al |
| 16407130 | 2006 | A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. | Percy MJ et al |
| 16966370 | 2006 | Placental 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 |
| 11574160 | 2001 | Characterization 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
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37975227 | 2024 | Prolyl hydroxylase 2 inhibits glycolytic activity in colorectal cancer via the NF‑κB signaling pathway. | 0 |
| 38287821 | 2024 | A Case-Control Study of the Associations between EGLN1 Gene Polymorphisms and COPD. | 0 |
| 38291512 | 2024 | Association of the C allele of rs479200 in the EGLN1 gene with COVID-19 severity in Indian population: a novel finding. | 2 |
| 38400673 | 2024 | Low nuclear expression of HIF-hydroxylases PHD2/EGLN1 and PHD3/EGLN3 are associated with poor recurrence-free survival in clear cell renal cell carcinoma. | 1 |
| 37975227 | 2024 | Prolyl hydroxylase 2 inhibits glycolytic activity in colorectal cancer via the NF‑κB signaling pathway. | 0 |
| 38287821 | 2024 | A Case-Control Study of the Associations between EGLN1 Gene Polymorphisms and COPD. | 0 |
| 38291512 | 2024 | Association of the C allele of rs479200 in the EGLN1 gene with COVID-19 severity in Indian population: a novel finding. | 2 |
| 38400673 | 2024 | Low nuclear expression of HIF-hydroxylases PHD2/EGLN1 and PHD3/EGLN3 are associated with poor recurrence-free survival in clear cell renal cell carcinoma. | 1 |
| 37317877 | 2023 | Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis. | 3 |
| 37661833 | 2023 | A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress. | 2 |
| 37847687 | 2023 | Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension. | 1 |
| 37317877 | 2023 | Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis. | 3 |
| 37661833 | 2023 | A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress. | 2 |
| 37847687 | 2023 | Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension. | 1 |
| 35538889 | 2022 | AMP-activated protein kinase α1 phosphorylates PHD2 to maintain systemic iron homeostasis. | 4 |
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-(egl-nine-homolog-1-(c-elegans))
