Kras regulatory elements and exon 4A determine mutation specificity in lung cancer.
Kras regulatory elements and exon 4A determine mutation specificity in lung cancer.
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DOI：
10.1038/ng.211
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发表时间：
2008-10
期刊：
影响因子：
30.8
通讯作者：
Balmain, Allan
中科院分区：
文献类型：
--
作者：
To, Minh D.;Wong, Christine E.;Karnezis, Anthony N.;Del Rosario, Reyno;Di Lauro, Roberto;Balmain, Allan
kras是肺癌中最常见的突变家族成员，而hras突变在分层上皮（如膀胱或皮肤）肿瘤中很常见（www.sanger.ac.uk/genetics/CGP/cosmic/）。通过将hras编码序列插入kraslocus的小鼠模型（HrasKI），我们证明了肺中krasmutations和皮肤肿瘤中hras mutations的特异性是由靶基因中的局部调控元件决定的。我们进一步表明，虽然ekras -4在小鼠发育中是不可缺少的，但它对于体内肺癌的发生和先前报道的野生型（WT）Krason的抑制作用是必需的，突变等位基因的转化特性。在正常肺上皮细胞亚群中检测到Kras-4A表达，但在肺肿瘤中表达水平非常低，表明Kras-4A在肿瘤起始而非肿瘤维持中起作用。这两种Kras亚型经历了不同的翻译后修饰，因此这些发现可能对设计抑制致癌Kras活性的治疗策略在预防和治疗癌症方面具有重要意义。
KRASis the most frequently mutatedrasfamily member in lung carcinomas, whereasHRASmutations are common in tumours from stratified epithelia such as bladder or skin (www.sanger.ac.uk/genetics/CGP/cosmic/). Using a mouse model (HrasKI) in which theHrascoding sequence was inserted into theKraslocus, we demonstrate that specificity forKrasmutations in lung andHras mutations in skin tumours is determined by local regulatory elements in the targetrasgenes. We further show that, whileKras-4Ais dispensable for mouse development, it is necessary both for lung carcinogenesisin vivoand for the previously reported inhibitory effect of wild-type (WT)Krason the transforming properties of the mutant allele. Kras-4A expression is detected in a sub-population of normal lung epithelial cells, but at very low levels in lung tumours, suggesting a role in tumour initiation rather than in tumour maintenance. The two Kras isoforms undergo different post-translational modifications, therefore these findings can have important implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in the prevention and treatment of cancer.
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DOI：
10.1073/pnas.82.23.7810
发表时间：
1985-01-01
影响因子：
11.1
作者：
GUERRERO, I;VILLASANTE, A;PELLICER, A
通讯作者：
PELLICER, A
DOI：
10.1073/pnas.86.9.3070
发表时间：
1989-05-01
影响因子：
11.1
作者：
YOU, M;CANDRIAN, U;ANDERSON, MW
通讯作者：
ANDERSON, MW
影响因子：
8
作者：
Ise, K;Nakamura, K;Katsuki, M
通讯作者：
Katsuki, M
影响因子：
5.3
作者：
Plowman, SJ;Williamson, DJ;Patek, CE
通讯作者：
Patek, CE
影响因子：
3.7
作者：
Patek, Charles E.;Arends, Mark J.;Hooper, Martin L.
通讯作者：
Hooper, Martin L.