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J. Biol. Chem., Vol. 276, Issue 47, 44323-44330, November 23, 2001
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From the Wellcome Trust Center for Human Genetics, The Henry
Wellcome Building of Genomic Medicine, Roosevelt Dr., Oxford OX3 7BN,
United Kingdom
Hypoxia-inducible factor (HIF) mediates a
widespread transcriptional response to hypoxia through binding to
cis-acting DNA sequences termed hypoxia response elements
(HREs). Activity of the transcriptional complex is suppressed in the
presence of oxygen by processes that include the targeting of
HIF-
Selection of Mutant CHO Cells with Constitutive Activation of
the HIF System and Inactivation of the von Hippel-Lindau Tumor
Suppressor*
subunits for ubiquitin-mediated proteolysis. To provide further
insights into these processes we constructed Chinese hamster
ovary (CHO) cells bearing stably integrated plasmids that expressed
HRE-linked surface antigens and used these cells in genetic screens for
mutants that demonstrated constitutive up-regulation of HRE activity.
From mutagenized cultures, clones were isolated that demonstrated
up-regulation of HRE activity and increased HIF-1 protein levels in
normoxic culture. Transfection and cell fusion studies suggested that
these cells possess recessive defects that affect one or more pathways involved in HIF- proteolysis. Two lines were demonstrated to harbor
truncating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. In these cells, defects in ubiquitylation of exogenous human HIF-1 in vitro could be complemented by
wild type pVHL, and re-expression of a wild type VHL gene
restored a normal pattern of HIF/HRE activity, demonstrating the
critical dependence of HIF regulation on pVHL in CHO cells. In
contrast, other mutant cells had no demonstrable mutation in the
VHL gene, and ubiquitylated exogenous HIF-1 normally,
suggesting that they contain defects at other points in the
oxygen-regulated processing of HIF- subunits.
*
This work was supported by grants from the Wellcome Trust
and the Medical Research Council, United Kingdom.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 44-1865-287531;
Fax: 44-1865-287533; E-mail: peter.ratcliffe@imm.ox.ac.uk.
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