HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O ₂ Sensing

Abstract

HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.

Effects of seasonal and latitudinal cold on oxidative stress parameters and activation of hypoxia inducible factor (HIF-1) in zoarcid fish

“…Of both subunits, only HIF-1a protein levels are regulated in an oxygen dependent manner by prolyl-hydroxylase enzymes (PHDs), whereas HIF-1ß is constitutively expressed and functional as nuclear translocator protein (ARNT). The prolyl hydroxylases target HIF1a for proteasomal degradation and, hence enable its removal from the cell, by hydroxylating two characteristic proline residues within a functional region of the protein, dubbed oxygen-dependent degradation domain (ODD, Ivan et al 2001;Fandrey et al 2006). The hydroxylating activity of the PHDs depends on the oxygen concentration in the cell and involves iron (II), ascorbate (for iron reduction) and 8-oxoglutarate as cofactors.…”

Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues

“…[1][2][3] Under normoxia, the transcription factor hypoxia inducible factor 1-R (HIF1R) is constitutively expressed and rapidly degraded, with a halflife of less than 5 min. 4 The degradation of HIF1R is regulated in part by PHD enzymes, which hydroxylate HIF1R proline residues 564 and 402, thereby enabling binding to the von Hippel-Lindau protein and subsequent proteasomic degradation.…”

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

“…The hydroxylation leads to its rapid proteosomal degradation in a von Hippel Lindau protein-dependent manner (Wang and Semenza, 1993a;Salceda and Caro, 1997;Huang et al, 1998). Hypoxia can be mimicked by the heavy metal cobalt chloride (CoCl 2 ), the iron-chelating agent, deferoxamine (DFX) or an inhibitor of the prolyl hydroxylases dimethyloxaloylglycine (DMOG), which all lead to the stabilisation of HIF-1a protein (Brahmachari and Joseph, 1973;Wang and Semenza, 1993b;Ivan et al, 2001). In tumours with a poor oxygen supply, HIF-1 target genes are induced, which help cell survival and encourage a more aggressive tumour phenotype by promoting growth, invasion and metastasis (Hockel et al, 1996;Vaupel et al, 2001;Yoon et al, 2001).…”