期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：19
页码：7979-7984
DOI：10.1073/pnas.0900343106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：We developed mice with germline endogenous expression of oncogenic Hras to study effects on development and mechanisms of tumor initiation. They had high perinatal mortality, abnormal cranial dimensions, defective dental ameloblasts, and nasal septal deviation, consistent with some of the features of human Costello syndrome. These mice developed papillomas and angiosarcomas, which were associated with HrasG12V allelic imbalance and augmented Hras signaling. Endogenous expression of HrasG12V was also associated with a higher mutation rate in vivo. Tumor initiation by HrasG12V likely requires augmentation of signal output, which in papillomas and angiosarcomas is achieved via increased Hras-gene copy number, which may be favored by a higher mutation frequency in cells expressing the oncoprotein.
