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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.

Pubmed ID: 19416908


  • Chen X
  • Mitsutake N
  • LaPerle K
  • Akeno N
  • Zanzonico P
  • Longo VA
  • Mitsutake S
  • Kimura ET
  • Geiger H
  • Santos E
  • Wendel HG
  • Franco A
  • Knauf JA
  • Fagin JA


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 12, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA50706
  • Agency: NCI NIH HHS, Id: CA72597
  • Agency: NCI NIH HHS, Id: P30 CA08748
  • Agency: NCI NIH HHS, Id: R24 CA83084
  • Agency: NIDDK NIH HHS, Id: T32 DK07313

Mesh Terms

  • Alleles
  • Animals
  • DNA Mutational Analysis
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neoplasms
  • Oncogenes
  • Signal Transduction
  • Tomography, X-Ray Computed
  • ras Proteins