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Nucleic Acids Research 2005 33(16):5190-5198; doi:10.1093/nar/gki839
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Published online 9 September 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Molecular Biology

Transcriptional repression of human cad gene by hypoxia inducible factor-1{alpha}

Ko-Fan Chen, Yen-Yu Lai, H. Sunny Sun1 and Shaw-Jenq Tsai*

Department of Physiology, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan 1Institute of Molecular Medicine, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan

*To whom correspondence should be addressed. Tel: +886 6 2353535 Ext. 5426; Fax: +886 6 2362780; Email: seantsai{at}mail.ncku.edu.tw

Received May 31, 2005. Revised August 30, 2005. Accepted August 30, 2005.

De novo biosynthesis of pyrimidine nucleotides provides essential precursors for DNA synthesis and cell proliferation. The first three steps of de novo pyrimidine biosynthesis are catalyzed by a multifunctional enzyme known as CAD (carbamoyl phosphate synthetase-aspartate carbamoyltransferase-dihydroorotase). In this work, a decrease in CAD expression is detected in numerous cell lines and primary culture human stromal cells incubated under hypoxia or desferrioxamine (DFO)-induced HIF-1{alpha} accumulation. A putative hypoxia response element (HRE) binding matrix is identified by analyzing human cad-gene promoter using a bioinformatic approach. Promoter activity assays, using constructs harboring the cad promoter (–710/+122) and the –67/HRE fragment (25-bases), respectively, demonstrate the suppression of reporter-gene expression under hypoxia. Suppression of cad-promoter activity is substantiated by forced expression of wild-type HIF-1{alpha} but abolished by overexpression of dominant-negative HIF-1{alpha}. A chromatin immunoprecipitation assay provides further evidence that HIF-1{alpha} binds to the cad promoter in vivo. These data demonstrate that the cad-gene expression is repressed by HIF-1{alpha}, which represents a functional link between hypoxia and cell-cycle arrest.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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