Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene.
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.
Chen
Xu
X
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Mitsutake
Norisato
N
LaPerle
Krista
K
Akeno
Nagako
N
Zanzonico
Pat
P
Longo
Valerie A
VA
Mitsutake
Shin
S
Kimura
Edna T
ET
Geiger
Hartmut
H
Santos
Eugenio
E
Wendel
Hans G
HG
Franco
Aime
A
Knauf
Jeffrey A
JA
Fagin
James A
JA
D000483:Alleles; D000818:Animals; D004252:DNA Mutational Analysis; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed / Q000379:methods; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
D018631:ras Proteins