Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression

Yuichi Makino, Renhai Cao, Kristian Svensson, Göran Bertilsson, Mikael Asman, Hirotoshi Tanaka, Yihai Cao, Anders Berkenstam and Lorenz Poellinger ()
Additional contact information
Yuichi Makino: Medical Nobel Institute, Karolinska Institutet
Renhai Cao: Karolinska Institutet
Kristian Svensson: Pharmacia Corporation
Göran Bertilsson: Pharmacia Corporation
Mikael Asman: Center for Genomics and Bioinformatics, Karolinska Institutet
Hirotoshi Tanaka: Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
Yihai Cao: Karolinska Institutet
Anders Berkenstam: Pharmacia Corporation
Lorenz Poellinger: Medical Nobel Institute, Karolinska Institutet

Nature, 2001, vol. 414, issue 6863, 550-554

Abstract: Abstract Alteration of gene expression is a crucial component of adaptive responses to hypoxia. These responses are mediated by hypoxia-inducible transcription factors (HIFs)1,2. Here we describe an inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, which is a basic helix-loop-helix (bHLH)/PAS protein structurally related to HIFs. IPAS contains no endogenous transactivation function but demonstrates dominant negative regulation of HIF-mediated control of gene expression. Ectopic expression of IPAS in hepatoma cells selectively impairs induction of genes involved in adaptation to a hypoxic environment, notably the vascular endothelial growth factor (VEGF) gene, and results in retarded tumour growth and tumour vascular density in vivo. In mice, IPAS was predominantly expressed in Purkinje cells of the cerebellum and in corneal epithelium of the eye. Expression of IPAS in the cornea correlates with low levels of expression of the VEGF gene under hypoxic conditions. Application of an IPAS antisense oligonucleotide to the mouse cornea induced angiogenesis under normal oxygen conditions, and demonstrated hypoxia-dependent induction of VEGF gene expression in hypoxic corneal cells. These results indicate a previously unknown mechanism for negative regulation of angiogenesis and maintenance of an avascular phenotype.

Date: 2001
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DOI: 10.1038/35107085

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