Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis.
To clarify the role of the H-Ras in vivo, we generated H-ras null mutant mice by gene targeting. In spite of the importance of the Ras in cell proliferation and differentiation, H-ras null mutant mice grew normally and were fertile. The oldest H-ras mutant mice grew to be more than 30 months old. We used the H-ras deficient mice to study the importance of the H-ras and other ras genes in the development of skin tumors induced by initiation with 7, 12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). We showed that H-ras null mutant mice develop approximately six times less papillomas compared with wild-type littermates after 20 weeks of TPA treatment. While all papillomas examined (17 out of 17) in wild-type mice have mutations of H-ras at codon 61, 13 (62%) out of 21 papillomas in H-ras null mutant mice have mutations of K-ras gene at codon 12, 13, or 61 and another eight (38%) papillomas have no mutations in these codons of K-ras or N-ras genes. This suggests that the activation of H-ras gene is critical in the wild-type mice, but the activation of K-ras gene can replace the H-ras activation in the initiation step of skin tumor development in the H-ras deficient mice. Oncogene (2000).
Ise
K
K
Department of Cell Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Nakamura
K
K
Nakao
K
K
Shimizu
S
S
Harada
H
H
Ichise
T
T
Miyoshi
J
J
Gondo
Y
Y
Ishikawa
T
T
Aiba
A
A
Katsuki
M
M
D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D017353:Gene Deletion; D011905:Genes, ras; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
D017931:DNA Primers; D004273:DNA, Neoplasm