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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.

Pubmed ID: 18372904

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

Nature genetics

Publication Data

May 29, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: K01 CA118425
  • Agency: NCI NIH HHS, Id: K01 CA118425-01A1
  • Agency: NCI NIH HHS, Id: K01 CA118425-02
  • Agency: NCI NIH HHS, Id: K01-CA118425
  • Agency: NCI NIH HHS, Id: P30 CA014051
  • Agency: NCI NIH HHS, Id: P30 CA014051-33
  • Agency: NCI NIH HHS, Id: P30 CA014051-34
  • Agency: NCI NIH HHS, Id: P30 CA014051-35
  • Agency: NCI NIH HHS, Id: P30 CA014051-36
  • Agency: NCI NIH HHS, Id: P30-CA14051
  • Agency: NCI NIH HHS, Id: P50-CA127003
  • Agency: NCI NIH HHS, Id: R01 CA072614
  • Agency: NCI NIH HHS, Id: R01 CA072614-03
  • Agency: NCI NIH HHS, Id: R01 CA072614-04
  • Agency: NCI NIH HHS, Id: R01 CA072614-04S1
  • Agency: NCI NIH HHS, Id: R01 CA072614-05
  • Agency: NCI NIH HHS, Id: R01 CA072614-05S1
  • Agency: NCI NIH HHS, Id: R01 CA072614-06
  • Agency: NCI NIH HHS, Id: R01 CA072614-07
  • Agency: NCI NIH HHS, Id: R01 CA072614-08
  • Agency: NCI NIH HHS, Id: R01 CA072614-09
  • Agency: NCI NIH HHS, Id: R01 CA072614-10
  • Agency: NIGMS NIH HHS, Id: R01 GM088827
  • Agency: NCI NIH HHS, Id: R01-CA72614
  • Agency: NCI NIH HHS, Id: R37 CA072614
  • Agency: NCI NIH HHS, Id: U01 CA084221
  • Agency: NCI NIH HHS, Id: U01 CA084221-01
  • Agency: NCI NIH HHS, Id: U01 CA084221-02
  • Agency: NCI NIH HHS, Id: U01 CA084221-03
  • Agency: NCI NIH HHS, Id: U01 CA084221-04
  • Agency: NCI NIH HHS, Id: U01 CA084221-05
  • Agency: NCI NIH HHS, Id: U01 CA084221-06
  • Agency: NCI NIH HHS, Id: U01 CA084221-07
  • Agency: NCI NIH HHS, Id: U01 CA084221-08
  • Agency: NCI NIH HHS, Id: U01 CA084221-09
  • Agency: NCI NIH HHS, Id: U01 CA084306
  • Agency: NCI NIH HHS, Id: U01 CA084306-01
  • Agency: NCI NIH HHS, Id: U01 CA084306-02
  • Agency: NCI NIH HHS, Id: U01 CA084306-03
  • Agency: NCI NIH HHS, Id: U01 CA084306-04
  • Agency: NCI NIH HHS, Id: U01 CA084306-05
  • Agency: NCI NIH HHS, Id: U01-CA84221
  • Agency: NCI NIH HHS, Id: U01-CA84306
  • Agency: NCI NIH HHS, Id: U54 CA112967
  • Agency: NCI NIH HHS, Id: U54 CA112967-010002
  • Agency: NCI NIH HHS, Id: U54 CA112967-020002
  • Agency: NCI NIH HHS, Id: U54 CA112967-030002
  • Agency: NCI NIH HHS, Id: U54 CA112967-040002
  • Agency: NCI NIH HHS, Id: U54-CA112967
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • 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