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.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Xu
X
Chen
Norisato
N
Mitsutake
Krista
K
LaPerle
Nagako
N
Akeno
Pat
P
Zanzonico
Valerie A
VA
Longo
Shin
S
Mitsutake
Edna T
ET
Kimura
Hartmut
H
Geiger
Eugenio
E
Santos
Hans G
HG
Wendel
Aime
A
Franco
Jeffrey A
JA
Knauf
James A
JA
Fagin
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