Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.
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.
Haigis
Kevin M
KM
Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Kendall
Krystle R
KR
Wang
Yufang
Y
Cheung
Ann
A
Haigis
Marcia C
MC
Glickman
Jonathan N
JN
Niwa-Kawakita
Michiko
M
Sweet-Cordero
Alejandro
A
Sebolt-Leopold
Judith
J
Shannon
Kevin M
KM
Settleman
Jeffrey
J
Giovannini
Marco
M
Jacks
Tyler
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D011905:Genes, ras; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D015398:Signal Transduction
D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases