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Activation of hypoxia-induced transcription in normoxia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
2005 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 306, no 1, 180-191 p.Article in journal (Refereed) Published
Abstract [en]

Hypoxia-inducible factor-1 (HIF-1), the master regulator of transcriptional responses to reduced oxygen tension (hypoxia) in mammalian cells, consists of one HIF-1alpha and one HIF-1beta subunit. In normoxia, HIF-1alpha subunits are hydroxylated on specific proline residues; modifications that signal ubiquitination and degradation of HIF-1alpha by the proteasome. To test the effect of saturating HIF-1alpha degradation, we generated a construct, denoted the saturating domain (SD), based on a region surrounding proline 564 (Pro564) in HIF-1alpha. Expression of the SD led to accumulation of endogenous HIF-1alpha proteins in nuclei of normoxic cells. The induced HIF-1alpha was functional as it activated expression from a hypoxia-regulated reporter gene and from the endogenous vascular endothelial growth facor-a (Vegf-a) and carbonic anhydrase 9 (Ca9) genes. The effect of the SD was dependent on Pro564 since a mutated SD, in which Pro564 had been replaced by a glycine residue, failed to bind the von Hippel-Lindau protein (pVHL) and to stabilise HIF-1alpha. Treatment of cells with the prolylhydroxylase inhibitor dimethyloxalylglycine, or the proteasome inhibitor MG-132, mimicked the effect of the SD. In conclusion, we show that blocking HIF-1alpha degradation, either by saturation, or inhibition of prolyl hydroxylases or proteosomal degradation, leads to nuclear localisation of active HIF-1alpha proteins.

Place, publisher, year, edition, pages
2005. Vol. 306, no 1, 180-191 p.
Keyword [en]
Hypoxia, Hypoixa-Inducible Factor-1, Vascular Endothelial Growth Factor, von Hippel-Lindau
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-73220DOI: 10.1016/j.yexcr.2005.01.017PubMedID: 15878343OAI: oai:DiVA.org:uu-73220DiVA: diva2:101131
Available from: 2005-06-01 Created: 2005-06-01 Last updated: 2010-08-10Bibliographically approved

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Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15878343&query_hl=1

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Hägg, MariaWennström, Stefan
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