International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B5. Positional Cloning of a Novel Tumor Suppressor Gene, Rit1

Y. Wakabayashi1, A. Matsuki1, Y. Takahashi1, H. Okano1, Y. Mishima1, O. Niwa2, and R. Kominami1
1Department of Biochemistry, Niigata University, School of Medicine, Asahimachi 1-757, Niigata 951-8122, and
2Radiation Biology Center, Kyoto University, Yoshida-Konoecho, Sakyou-Ku, Kyoto 606-8315, Japan

Mouse genetic systems offer a number of useful features for genetic and physical mapping toward positional cloning. However, no success was reported of novel tumor suppressor genes. Here we report the isolation of a gene of that type by using the mouse model system. A genome wide LOH analysis was performed for gamma-ray induced mouse thymic lymphomas, and three loci on mouse chromosomes 11, 12, 16 showing high frequencies of LOH were detected. To narrow further the interval harboring a putative tumor suppressor gene on chromosome 12, a high-density scan has been carried out for informative 361 thymic lymphomas. Construction of BAC contigs and sequence analysis revealed a novel type of zinc finger protein, Rit1. It consists of four exons and contains two separated clusters of zinc finger motifs. Among 146 lymphomas with allelic loss, we found fourteen homozygous deletions, twelve of which were restricted to exon 2 and/or exon 3. Two microdeletions and three missense mutations were detected. Seventeen of the nineteen bi-allelic changes were found in p53 wild-type lymphomas (26%) and only two in p53 null lymphomas (3.7%). These results suggest that Rit1 functions as a tumor suppressor gene with a functional association to p53.

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