Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1).
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.
Tamura
Yasushi
Y
Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi 1-757, Niigata 951-8122, Japan.
Maruyama
Masaki
M
Mishima
Yukio
Y
Fujisawa
Hiromi
H
Obata
Miki
M
Kodama
Yasumitsu
Y
Yoshikai
Yoshihiro
Y
Aoyagi
Yutaka
Y
Niwa
Ohtsura
O
Schaffner
Walter
W
Kominami
Ryo
R
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D007113:Immunity, Innate; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011392:Proline; D012694:Serine; D013953:Thymus Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D000097809:Transcription Factor MTF-1
D017931:DNA Primers; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011392:Proline; D012694:Serine; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1