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J. Biol. Chem., Vol. 280, Issue 11, 10572-10577, March 18, 2005

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Gene Trap Mutagenesis-based Forward Genetic Approach Reveals That the Tumor Suppressor OVCA1 Is a Component of the Biosynthetic Pathway of Diphthamide on Elongation Factor 2^*

Yoshitaka Nobukuni, Kenji Kohno¶, and Kiyoshi Miyagawa

From the Department of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan and the ^¶Department of Molecular and Cell Genetics, Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Nara 630-0101, Japan

OVCA1 is a tumor suppressor identified by positional cloning from chromosome 17p13.3, a hot spot for chromosomal aberration in breast and ovarian cancers. It has been shown that expression of OVCA1 is reduced in some tumors and that it regulates cell proliferation, embryonic development, and tumorigenesis. However, the biochemical function of OVCA1 has remained unknown. Recently, we isolated a novel mutant resistant to diphtheria toxin and Pseudomonas exotoxin A from the gene trap insertional mutants library of Chinese hamster ovary cells. In this mutant, the Ovca1 gene was disrupted by gene trap mutagenesis, and this disruption well correlated with the toxin-resistant phenotype. We demonstrated direct evidence that the tumor suppressor OVCA1 is a component of the biosynthetic pathway of diphthamide on elongation factor 2, the target of bacterial ADP-ribosylating toxins. A functional genetic approach utilizing the random gene trap mutants library of mammalian cells should become a useful strategy to identify the genes responsible for specific phenotypes.

Received for publication, November 17, 2004 , and in revised form, December 14, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AB194396.

^* This work was supported by Grants-in-Aid for Scientific Research (A) 15659074 and (B) 12204091 from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a grant from the ONO Medical Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Dept. of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Tel.: 81-82-257-5829; Fax: 81-82-256-7102; E-mail: nobukuni{at}hiroshima-u.ac.jp.

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