Chen Xu, Mitsutake Norisato, LaPerle Krista, Akeno Nagako, Zanzonico Pat, Longo Valerie A, Mitsutake Shin, Kimura Edna T, Geiger Hartmut, Santos Eugenio, Wendel Hans G, Franco Aime, Knauf Jeffrey A, Fagin James A
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7979-84. doi: 10.1073/pnas.0900343106. Epub 2009 Apr 29.
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 Hras(G12V) allelic imbalance and augmented Hras signaling. Endogenous expression of Hras(G12V) was also associated with a higher mutation rate in vivo. Tumor initiation by Hras(G12V) 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.
我们构建了致癌性Hras基因在生殖系中内源性表达的小鼠，以研究其对发育的影响及肿瘤起始机制。这些小鼠围产期死亡率高，颅骨尺寸异常，牙釉质细胞有缺陷，鼻中隔偏曲，与人类科斯特洛综合征的一些特征相符。这些小鼠发生了乳头状瘤和血管肉瘤，这与Hras（G12V）等位基因失衡及Hras信号增强有关。Hras（G12V）的内源性表达还与体内较高的突变率相关。Hras（G12V）引发肿瘤可能需要增强信号输出，在乳头状瘤和血管肉瘤中，这是通过增加Hras基因拷贝数实现的，而表达癌蛋白的细胞中较高的突变频率可能有利于这种情况发生。
