Article abstract
Nature Genetics 40, 600 - 608 (2008)
Published online: 30 March 2008 | doi:10.1038/ng.115
Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon
Kevin M Haigis1,2, Krystle R Kendall2, Yufang Wang2, Ann Cheung1, Marcia C Haigis3, Jonathan N Glickman4, Michiko Niwa-Kawakita5, Alejandro Sweet-Cordero6, Judith Sebolt-Leopold7, Kevin M Shannon8, Jeffrey Settleman2, Marco Giovannini5 & Tyler Jacks1,9
Abstract
Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-RasG12D in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-RasG12D did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.
- Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
- Massachusetts General Hospital, Center for Cancer Research and Molecular Pathology Unit, Charlestown, Massachusetts 02129, USA.
- Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
- Institut National de la Santé et de la Recherche Médicale U674, Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain et Institut Universitaire d'Hématologie, Paris, France.
- Department of Pediatrics and Cancer Biology Program, Stanford University School of Medicine, Palo Alto, California 94305, USA.
- JS Leopold Consulting, Ann Arbor, Michigan 48105, USA.
- Department of Pediatrics, University of California San Francisco, San Francisco, California 94143, USA.
- Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Correspondence to: Tyler Jacks1,9 e-mail: tjacks@mit.edu
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