Title | Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Haigis, KM, Kendall, KR, Wang, Y, Cheung, A, Haigis, MC, Glickman, JN, Niwa-Kawakita, M, Sweet-Cordero, A, Sebolt-Leopold, J, Shannon, KM, Settleman, J, Giovannini, M, Jacks, T |
Journal | Nat Genet |
Volume | 40 |
Issue | 5 |
Pagination | 600-8 |
Date Published | 2008 May |
ISSN | 1546-1718 |
Keywords | Animals, Apoptosis, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Colonic Neoplasms, Epithelium, Genes, ras, Homeostasis, Humans, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases, Mutation, Proto-Oncogene Proteins B-raf, Signal Transduction |
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. |
DOI | 10.1038/ng.115 |
Alternate Journal | Nat. Genet. |
PubMed ID | 18372904 |
PubMed Central ID | PMC2410301 |
Grant List | K01 CA118425-01A1 / CA / NCI NIH HHS / United States K01 CA118425-02 / CA / NCI NIH HHS / United States K01-CA118425 / CA / NCI NIH HHS / United States P30 CA014051-33 / CA / NCI NIH HHS / United States P30 CA014051-34 / CA / NCI NIH HHS / United States P30 CA014051-35 / CA / NCI NIH HHS / United States P30 CA014051-36 / CA / NCI NIH HHS / United States P30-CA14051 / CA / NCI NIH HHS / United States P50-CA127003 / CA / NCI NIH HHS / United States R01 CA072614-03 / CA / NCI NIH HHS / United States R01 CA072614-04 / CA / NCI NIH HHS / United States R01 CA072614-04S1 / CA / NCI NIH HHS / United States R01 CA072614-05 / CA / NCI NIH HHS / United States R01 CA072614-05S1 / CA / NCI NIH HHS / United States R01 CA072614-06 / CA / NCI NIH HHS / United States R01 CA072614-07 / CA / NCI NIH HHS / United States R01 CA072614-08 / CA / NCI NIH HHS / United States R01 CA072614-09 / CA / NCI NIH HHS / United States R01 CA072614-10 / CA / NCI NIH HHS / United States R01 GM088827-03 / GM / NIGMS NIH HHS / United States R01-CA72614 / CA / NCI NIH HHS / United States R37 CA072614 / CA / NCI NIH HHS / United States U01 CA084221-01 / CA / NCI NIH HHS / United States U01 CA084221-02 / CA / NCI NIH HHS / United States U01 CA084221-03 / CA / NCI NIH HHS / United States U01 CA084221-04 / CA / NCI NIH HHS / United States U01 CA084221-05 / CA / NCI NIH HHS / United States U01 CA084221-06 / CA / NCI NIH HHS / United States U01 CA084221-07 / CA / NCI NIH HHS / United States U01 CA084221-08 / CA / NCI NIH HHS / United States U01 CA084221-09 / CA / NCI NIH HHS / United States U01 CA084306-01 / CA / NCI NIH HHS / United States U01 CA084306-02 / CA / NCI NIH HHS / United States U01 CA084306-03 / CA / NCI NIH HHS / United States U01 CA084306-04 / CA / NCI NIH HHS / United States U01 CA084306-05 / CA / NCI NIH HHS / United States U01-CA84221 / CA / NCI NIH HHS / United States U01-CA84306 / CA / NCI NIH HHS / United States U54 CA112967-010002 / CA / NCI NIH HHS / United States U54 CA112967-020002 / CA / NCI NIH HHS / United States U54 CA112967-030002 / CA / NCI NIH HHS / United States U54 CA112967-040002 / CA / NCI NIH HHS / United States U54-CA112967 / CA / NCI NIH HHS / United States / / Howard Hughes Medical Institute / United States / / Howard Hughes Medical Institute / United States |