Endogenous oncogenic K-ras G12D stimulates proliferation and widespread neoplastic and developmental defects

• Published in: Cancer cell Vol. 5; no. 4; pp. 375 - 387
• Main Authors: Tuveson, David A, Shaw, Alice T, Willis, Nicholas A, Silver, Daniel P, Jackson, Erica L, Chang, Sandy, Mercer, Kim L, Grochow, Rebecca, Hock, Hanno, Crowley, Denise, Hingorani, Sunil R, Zaks, Tal, King, Catrina, Jacobetz, Michael A, Wang, Lifu, Bronson, Roderick T, Orkin, Stuart H, DePinho, Ronald A, Jacks, Tyler
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2004
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/S1535-6108(04)00085-6

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-ras G12D allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras G12D -expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras G12D 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.