Human Molecular Genetics Advance Access originally published online on July 14, 2004
Human Molecular Genetics 2004 13(18):2061-2074; doi:10.1093/hmg/ddh215
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved
Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney
1Department of Pathology and 2Department of Pediatrics, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver, BC, Canada V5Z 4H4, 3Department of Medical Biophysics and 4Department of Immunology, University of Toronto, Toronto, Ontario, Canada, 5Department of Pediatrics, IWK Grace Health Centre, Halifax, Nova Scotia, Canada B3L 3G9, 6Cross Cancer Institute, Edmonton AB, Canada T6G 1Z2, 7Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4S6 and 8Institute for Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
Received May 7, 2004; Accepted July 6, 2004
We have analyzed the chromosome 6q21 breakpoint of a non-constitutional t(6;15)(q21;q21) rearrangement in sporadic Wilms' tumor. This identified a novel gene encoding a protein with six N-terminal ankyrin repeats linked to a C-terminal HECT ubiquitin-protein ligase domain. We therefore designated this gene HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1). HACE1 is widely expressed in human tissues, including mature and fetal kidney. We show that Hace1 protein possesses intrinsic ubiquitin ligase activity, utilizes UbcH7 as a candidate partner E2 enzyme and localizes predominantly to the endoplasmic reticulum. Although the HACE1 locus was not directly interrupted by the translocation in the index Wilms' case, its expression was markedly lower in tumor tissue compared with adjacent normal kidney. Moreover, HACE1 expression was virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney. We found no evidence of HACE1 mutations or deletions, but hypermethylation of two upstream CpG islands correlates with low HACE1 expression in tumor samples. Our findings implicate Hace1 as a novel ubiquitin-protein ligase and demonstrate that its expression is very low in primary Wilms' tumors.
* To whom correspondence should be addressed. Tel: +1 6048752936; Fax: +1 6048753417; Email: psor{at}interchange.ubc.ca
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