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Br J Cancer. 2007 Apr 23;96(8):1284-92. Epub 2007 Mar 27.

Target gene selectivity of hypoxia-inducible factor-alpha in renal cancer cells is conveyed by post-DNA-binding mechanisms.

Author information

1
The Henry Wellcome Building for Molecular Physiology, Oxford, UK.

Abstract

Inactivation of the von Hippel-Lindau tumour suppressor in renal cell carcinoma (RCC) leads to failure of proteolytic regulation of the alpha subunits of hypoxia-inducible factor (HIF), constitutive upregulation of the HIF complex, and overexpression of HIF target genes. However, recent studies have indicated that in this setting, upregulation of the closely related HIF-alpha isoforms, HIF-1alpha and HIF-2alpha, have contrasting effects on tumour growth, and activate distinct sets of target genes. To pursue these findings, we sought to elucidate the mechanisms underlying target gene selectivity for HIF-1alpha and HIF-2alpha. Using chromatin immunoprecipitation to probe binding to hypoxia response elements in vivo, and expression of chimaeric molecules bearing reciprocal domain exchanges between HIF-1alpha and HIF-2alpha molecules, we show that selective activation of HIF-alpha target gene expression is not dependent on selective DNA-binding at the target locus, but depends on non-equivalent C-terminal portions of these molecules. Our data indicate that post-DNA binding mechanisms that are dissimilar for HIF-1alpha and HIF-2alpha determine target gene selectivity in RCC cells.

PMID:
17387348
PMCID:
PMC2360163
DOI:
10.1038/sj.bjc.6603675
[Indexed for MEDLINE]
Free PMC Article

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