Author/Authors :
Tuveson، نويسنده , , David A and Shaw، نويسنده , , Alice T and Willis، نويسنده , , Nicholas A and Silver، نويسنده , , Daniel P and Jackson، نويسنده , , Erica L and Chang، نويسنده , , Sandy and Mercer، نويسنده , , Kim L and Grochow، نويسنده , , Rebecca and Hock، نويسنده , , Hanno and Crowley، نويسنده , , Denise and Hingorani، نويسنده , , Sunil R and Zaks، نويسنده , , Tal and King، نويسنده , , Catrina and Jacobetz، نويسنده , , Michael A and Wang، نويسنده , , Lifu and Bronson، نويسنده , , Roderick T and Orkin، نويسنده , , Stuart H and DePinho، نويسنده , , Ronald A and Jacks، نويسنده , , Tyler، نويسنده ,
Abstract :
Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-rasG12D allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-rasG12D-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-rasG12D is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.
