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Title 

Differential sensitivity of hypoxia inducible factor hydroxylation sites to hypoxia and hydroxylase inhibitors

Authors 

Y M TianK K YeohMyung Kyu LeeT ErikssonB M KesslerH B KramerM J EdelmannC WillamC W PughC J SchofieldP J Ratcliffe

Publisher 

American Society for Biochemistry and Molecular Biology

Issue Date 

2011

Citation 

Journal of Biological Chemistry, vol. 286, no. 15, pp. 13041-13051

Abstract 

Hypoxia inducible factor (HIF) is regulated by dual pathways involving oxygen-dependent prolyl and asparaginyl hydroxylation of its α-subunits. Prolyl hydroxylation at two sites within a central degradation domain promotes association of HIF-α with the von Hippel-Lindau ubiquitin E3 ligase and destruction by the ubiquitin-proteasome pathways. Asparaginyl hydroxylation blocks the recruitment of p300/CBP co-activators to a C-terminal activation domain in HIF-α. These hydroxylations are catalyzed by members of the Fe(II) and 2-oxoglutarate (2-OG) oxygenase family. Activity of the enzymes is suppressed by hypoxia, increasing both the abundance and activity of the HIF transcriptional complex. We have used hydroxy residue-specific antibodies to compare and contrast the regulation of each site of prolyl hydroxylation (Pro402, Pro564) with that of asparaginyl hydroxylation (Asn803) in human HIF-1α. Our findings reveal striking differences in the sensitivity of these hydroxylations to hypoxia and to different inhibitor types of 2-OG oxygenases. Hydroxylation at the three sites in endogenous human HIF-1α proteins was suppressed by hypoxia in the order Pro402 > Pro564 > Asn803. In contrast to some predictions from in vitro studies, prolyl hydroxylation was substantially more sensitive than asparaginyl hydroxylation to inhibition by iron chelators and transition metal ions; studies of a range of different small molecule 2-OG analogues demonstrated the feasibility of selectively inhibiting either prolyl or asparaginyl hydroxylation within cells.

ISSN 

0021-9258

Link 

http://dx.doi.org/10.1074/jbc.M110.211110

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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