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Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation

Masson, N; Willam, C; Maxwell, PH; Pugh, CW; Ratcliffe, PJ; (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J , 20 (18) 5197 - 5206.

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Abstract

Oxygen-dependent proteolytic destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits plays a central role in regulating transcriptional responses to hypoxia. Recent studies have defined a key function for the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase (VHLE3) in this process, and have defined an interaction with HIF-1 alpha that is regulated by prolyl hydroxylation. Here we show that two independent regions within the HIF-1 alpha oxygen-dependent degradation domain (ODDD) are targeted for ubiquitylation by VHLE3 in a manner dependent upon prolyl hydroxylation. In a series of in vitro and in vivo assays, we demonstrate the independent and non-redundant operation of each site in regulation of the HIF system. Both sites contain a common core motif, but differ both in overall sequence and in the conditions under which they bind to the VHLE3 ligase complex. The definition of two independent destruction domains implicates a more complex system of pVHL-HIF-alpha interactions, but reinforces the role of prolyl hydroxylation as an oxygen-dependent destruction signal.

Type:Article
Title:Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation
Keywords:destruction domain, hypoxia-inducible factor alpha, prolyl hydroxylation, ubiquitylation, von Hippel-Lindau protein, TUMOR-SUPPRESSOR PROTEIN, FACTOR 1-ALPHA HIF-1-ALPHA, TRANSCRIPTIONAL ACTIVITY, DEPENDENT PROTEOLYSIS, FACTOR-I, SUBUNIT, UBIQUITINATION, STABILIZATION, BINDING, HIF-1
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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