Differential Effects of Oncogenic K-Ras and N-Ras on Proliferation, Differentiation and Tumor Progression in the Colon

Overview

Journal Nat Genet

Specialty Genetics

Date 2008 Apr 1

PMID 18372904

Citations 341

Authors

Kevin M Haigis

Krystle R Kendall

Yufang Wang

Ann Cheung

Marcia C Haigis

Jonathan N Glickman

Michiko Niwa-Kawakita

Alejandro Sweet-Cordero

Judith Sebolt-Leopold

Kevin M Shannon

Jeffrey Settleman

Marco Giovannini

Tyler Jacks

Affiliations

Soon will be listed here.

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-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) 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.

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