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  • Original Paper
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Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1)

Oncogene volume 24, pages 399–406 (2005)Cite this article

Abstract

Genetic predisposition to cancers is significant to public health because a high proportion of cancers probably arise in a susceptible human subpopulation. Using a mouse model of γ-ray-induced thymic lymphomas, we performed linkage analysis and haplotype mapping that suggested Mtf-1, metal-responsive transcription factor-1 (Mtf-1), as a candidate lymphoma susceptibility gene. Sequence analysis revealed a polymorphism of Mtf-1 that alters the corresponding amino acid at position 424 in the proline-rich domain from a serine in susceptibility strains to proline in resistant strains. The transcriptional activity of Mtf-1 encoding serine and proline was compared by transfecting the DNA to Mtf-1-null cells, and the change to proline conferred a higher metal responsiveness in transfections. Furthermore, the resistant congenic strains possessing the Mtf-1 allele of proline type exhibited higher radiation inducibility of target genes than susceptible background strains having the Mtf-1 allele of serine type. Since products of the targets such as metallothionein are able to suppress cellular stresses generated by irradiation, these results suggest that highly inducible strains having Mtf-1 of proline type are refractory to radiation effects and hence are resistant to lymphoma development.

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Acknowledgements

We thank Dr George Hausmann for critical reading of the manuscript. This work was supported by grants-in-aid of Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan.

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Authors and Affiliations

  1. Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi 1-757, Niigata, 951-8122, Japan

    Yasushi Tamura, Masaki Maruyama, Yukio Mishima, Hiromi Fujisawa, Miki Obata, Yasumitsu Kodama, Yoshihiro Yoshikai, Yutaka Aoyagi & Ryo Kominami

  2. Center for Transdisciplinary Research, Niigata University, Asahimachi 1-757, Niigata, 951-8122, Japan

    Yukio Mishima & Ryo Kominami

  3. Radiation Biology Center, Kyoto University, Yoshida-Konoecho, Sakyou-Ku, Kyoto, 606-8315, Japan

    Ohtsura Niwa

  4. Institute for Molecular Biology, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland

    Walter Schaffner

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  1. Yasushi Tamura
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Correspondence to Ryo Kominami.

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Tamura, Y., Maruyama, M., Mishima, Y. et al. Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1). Oncogene 24, 399–406 (2005). https://doi.org/10.1038/sj.onc.1208197

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