Untitled

Abstract

BackgroundThe 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 α subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1α 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).ResultsPatients with IE were screened for changes in the HIF-1α 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.ConclusionThe Pro582Ser change represents a common polymorphism of HIF-1α that does not impair HIF-1α prolyl hydroxylation. Although the Pro582Ser polymorphism is located in the ODD domain of HIF-1α it does not diminish the association of HIF-1α with VHL. Thus, it is unlikely that this polymorphism accounts for the erythrocytosis in the group of IE patients studied.

Impact of the Hypoxia-Inducible Factor-1 α (HIF1A) Pro582Ser Polymorphism on Diabetes Nephropathy

“…However, Pro582 has no essential role in HIF-1α stability because its mutation with serine does not affect HIF-1α levels, neither in normoxia nor hypoxia (Fig. 2 A ), which is in perfect agreement with previous observations (31). Moreover Pro582Ser does not have a central role in the destabilizing effect of glucose on HIF-1α (9) because we observed a clear destabilization of the Pro582Ser construct in hyperglycemia (Fig.…”

A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis

“…Idiopathic erythrocytosis patients with a family history were selected from our registry (19,40). Ethical approval was obtained from the Queen's University Research Ethics Committee, and written, informed consent was obtained from all individuals.…”

VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

“…A common SNP mapping in the ODD domain in exon 12 of HIF-1a (C1772T, Pro582Ser) has been described in the literature [13,29]. Although not involved in the process of hydroxylation [14], this SNP may confer susceptibility to renal cancerogenesis and progression. Supporting this hypothesis, Kim et al [8] showed that the Pro582Ser change contributes to the development of metastases.…”

“…This SNP leads to a proline to serine substitution at codon 582 [13,14]. Although C1772T has been shown not to affect the hydroxylation process [15], it might confer susceptibility to RCC and its presence has been demonstrated to correlate with the development of metastases [14]. Here, we evaluated the prognostic significance of such SNP in ccRCC patients.…”

“…A relatively recent study from Kim et al [12] showed that a SNP mapping in the HIF-1a ODD domain (C1772T, rs11549465) associates with HIF1a protein expression in breast cancer. This SNP leads to a proline to serine substitution at codon 582 [13,14]. Although C1772T has been shown not to affect the hydroxylation process [15], it might confer susceptibility to RCC and its presence has been demonstrated to correlate with the development of metastases [14].…”