Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 19, Pages 7979-7984Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0900343106
Keywords
allele copy number; angiosarcoma; Costello syndrome; papilloma; senescence
Categories
Funding
- National Institutes of Health [CA72597, CA50706, T32 DK07313, R24 CA83084, P30 CA08748]
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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(G12)V was also associated with a higher mutation rate in vivo. Tumor initiation by Hras(G12)V 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.
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