Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase.
Oxygen radicals, which can be produced through normal cellular metabolism, are thought to play an important role in mutagenesis and tumorigenesis. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is most important because of its abundance and mutagenicity. The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations. By means of gene targeting, we have established MTH1 gene-knockout cell lines and mice. When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers, and stomachs of MTH1-deficient mice, as compared with wild-type mice. The MTH1-deficient mouse will provide a useful model for investigating the role of the MTH1 protein in normal conditions and under oxidative stress.
Tsuzuki
T
T
Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan. tsuzuki@med.kyushu-u.ac.jp
Egashira
A
A
Igarashi
H
H
Iwakuma
T
T
Nakatsuru
Y
Y
Tominaga
Y
Y
Kawate
H
H
Nakao
K
K
Nakamura
K
K
Ide
F
F
Kura
S
S
Nakabeppu
Y
Y
Katsuki
M
M
Ishikawa
T
T
Sekiguchi
M
M
D000230:Adenocarcinoma / Q000235:genetics; D000483:Alleles; D000818:Animals; D001755:Blastocyst; D015153:Blotting, Western; D002678:Chimera; D002999:Clone Cells; D003433:Crosses, Genetic; D004249:DNA Damage; D017931:DNA Primers; D045643:DNA Repair Enzymes; D005091:Exons; D005260:Female; D008099:Liver / Q000201:enzymology; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011995:Recombination, Genetic; D015183:Restriction Mapping; D013274:Stomach Neoplasms / Q000235:genetics
D017931:DNA Primers; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes