Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.

TitleDifferential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.
Publication TypeJournal Article
Year of Publication2008
AuthorsHaigis, 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
JournalNat Genet
Volume40
Issue5
Pagination600-8
Date Published2008 May
ISSN1546-1718
KeywordsAnimals, 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.

DOI10.1038/ng.115
Alternate JournalNat. Genet.
PubMed ID18372904
PubMed Central IDPMC2410301
Grant ListK01 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

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