A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1alpha (HIF-1alpha) does not impair Pro-564 hydroxylation.
BACKGROUND
The hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis and erythropoiesis. Under normoxic conditions, the alpha subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1alpha in the oxygen-dependent degradation (ODD) domain. This allows subsequent recognition by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, prolyl hydroxylation of HIF is inhibited, allowing it to escape VHL-mediated degradation. The transcriptional regulation of the erythropoietin gene by HIF raises the possibility that HIF may play a role in disorders of erythropoiesis, such as idiopathic erythrocytosis (IE).


RESULTS
Patients with IE were screened for changes in the HIF-1alpha coding sequence, and a change in the ODD domain that converts Pro-582 to Ser was identified in several patients. This same change, however, was also detected at a significant frequency, 0.073, in unaffected controls compared to 0.109 in the IE patient group. In vitro hydroxylation assays examining this amino acid change failed to reveal a discernible effect on HIF hydroxylation at Pro-564.


CONCLUSIONS
The Pro582Ser change represents a common polymorphism of HIF-1alpha that does not impair HIF-1alpha prolyl hydroxylation. Although the Pro582Ser polymorphism is located in the ODD domain of HIF-1alpha it does not diminish the association of HIF-1alpha with VHL. Thus, it is unlikely that this polymorphism accounts for the erythrocytosis in the group of IE patients studied.
Percy
Melanie J
MJ
Department of Haematology, Belfast City Hospital, Belfast, Northern Ireland, BT9 7AB, UK. melanie.percy@bll.n-i.nhs.uk
Mooney
Sharon M
SM
McMullin
Mary Frances
MF
Flores
Adrian
A
Lappin
Terence R J
TR
Lee
Frank S
FS
D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D020125:Mutation, Missense; D010100:Oxygen / Q000502:physiology; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D004247:DNA; D011392:Proline; D010100:Oxygen