Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1).
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| 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 gamma-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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| Authors | Yasushi Tamura, Masaki Maruyama, Yukio Mishima, Hiromi Fujisawa, Miki Obata, Yasumitsu Kodama, Yoshihiro Yoshikai, Yutaka Aoyagi, Ohtsura Niwa, Walter Schaffner, Ryo Kominami |
| Journal | Oncogene (Oncogene) Vol. 24 Issue 3 Pg. 399-406 (Jan 13 2005) ISSN: 0950-9232 [Print] England |
| PMID | 15516976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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