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FEBS Lett. 2006 Nov 13;580(26):6182-6. Epub 2006 Oct 18.

Immunophilin-ligands FK506 and CsA inhibit HIF1alpha expression by a VHL- and ubiquitin-independent mechanism.

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1
Cardeza Foundation for Hematologic Research and Department of Medicine, Thomas Jefferson University, 1015 Walnut St. Room 807, Philadelphia, PA 19107, USA.

Abstract

Hypoxia inducible factor-1alpha (HIF1alpha) plays a key role in the regulation of genes controlling oxygen supply, glucose metabolism and angiogenesis. Its expression in tumors appears to confer an adaptive advantage to their hypoxic microenvironment. We have evaluated the effect of the immunophilin ligands FK506 and cyclosporin A on HIF1alpha levels in different tumor cell lines. Our results indicate that both drugs are potent suppressors of HIF1alpha expression by accelerating the proteasomal degradation of the protein. Unexpectedly, the suppressive effect of these compounds was found to be independent of the presence of von Hippel Lindau factor and the degree of hydroxylation of the HIF1alpha protein. Moreover, HIF1alpha degradation induced by these compounds did not required ubiquitination, as it was also induced in E1 ligase-incompetent cells.

PMID:
17067582
DOI:
10.1016/j.febslet.2006.10.019
[Indexed for MEDLINE]
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