Nucleic Acids Research Advance Access originally published online on October 25, 2007
Nucleic Acids Research 2007 35(21):7372-7388; doi:10.1093/nar/gkm896
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Nucleic Acids Research, 2007, Vol. 35, No. 21 7372-7388
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-com
Molecular Biology |
Expression of the CTCF-paralogous cancer-testis gene, brother of the regulator of imprinted sites (BORIS), is regulated by three alternative promoters modulated by CpG methylation and by CTCF and p53 transcription factors
1Section of Molecular Pathology, Laboratory of Immunopathology, NIAID, NIH, Rockville, MD 20815, USA, 2Departamento de Biologia Molecular and Unidad de Biomedicina-CSIC, Universidad de Cantabria, 39011 Santander, Spain and 3Institute of Pathology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
* To whom correspondence should be addressed. Tel: +41 21 314 7153; Fax: +41 21 314 7115; Email: jean.benhattar{at}chuv.ch Correspondence may also be addressed to Victor Lobanenkov. Tel: +1 301 496 1150; Fax: +1 301 402 0077; Email: vlobanenkov{at}niaid.nih.gov
Received April 23, 2007. Revised October 3, 2007. Accepted October 4, 2007.
BORIS, like other members of the ‘cancer/testis antigen’ family, is normally expressed in testicular germ cells and repressed in somatic cells, but is aberrantly activated in cancers. To understand regulatory mechanisms governing human BORIS expression, we characterized its 5'-flanking region. Using 5' RACE, we identified three promoters, designated A, B and C, corresponding to transcription start sites at –1447, –899 and –658 bp upstream of the first ATG. Alternative promoter usage generated at least five alternatively spliced BORIS mRNAs with different half-lives determined by varying 5'-UTRs. In normal testis, BORIS is transcribed from all three promoters, but 84% of the 30 cancer cell lines tested used only promoter(s) A and/or C while the others utilized primarily promoters B and C. The differences in promoter usage between normal and cancer cells suggested that they were subject to differential regulation. We found that DNA methylation and functional p53 contributes to the negative regulation of each promoter. Moreover, reduction of CTCF in normally BORIS-negative human fibroblasts resulted in derepression of BORIS promoters. These results provide a mechanistic basis for understanding cancer-related associations between haploinsufficiency of CTCF and BORIS derepression, and between the lack of functional p53 and aberrant activation of BORIS.
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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