Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis
Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis
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DOI：
10.1038/sj.onc.1203600
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发表时间：
2000-06-15
期刊：
影响因子：
8
通讯作者：
Katsuki, M
中科院分区：
文献类型：
--
作者：
Ise, K;Nakamura, K;Katsuki, M
为了阐明H-Ras在体内的作用，我们通过基因打靶产生H-ras无效突变小鼠。尽管Ras在细胞增殖和分化中的重要性，但H-ras无效突变小鼠生长正常且具有生育能力。年龄最大的H-ras突变小鼠生长到30个月以上。我们使用H-ras缺陷小鼠来研究H-ras和其他ras基因在皮肤肿瘤发展中的重要性，所述皮肤肿瘤由7，12-二甲基苯并（a）蒽（DMBA）引发，然后用12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）促进。我们表明，在TPA处理20周后，与野生型同窝小鼠相比，H-ras无效突变小鼠发展乳头状瘤大约少6倍。在野生型小鼠中检测的所有乳头状瘤（17/17）在密码子61处具有H-ras突变，而在H-ras无效突变小鼠中的21个乳头状瘤中的13个（62%）在密码子12、13或61处具有K-ras基因突变，另外8个（38%）乳头状瘤在K-ras或N-ras基因的这些密码子中没有突变。这表明H-ras基因的激活在野生型小鼠中是至关重要的，而K-ras基因的激活可以在H-ras缺陷小鼠皮肤肿瘤发生的起始步骤中取代H-ras的激活。
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-vas 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.