Oncogenic K-RAS subverts the antiapoptotic role of N-RAS and alters modulation of the N-RAS:gelsolin complex.
Activating mutations in members of the RAS family of genes are among the most common genetic events in human tumorigenesis. Once thought to be functionally interchangeable, it is increasingly recognized that the classical members of this protein family (H-RAS, N-RAS and K-RAS4B) exhibit unique and shared functions that are highly context-dependent. Herein, we demonstrate that the presence of an oncogenic KRAS allele results in elevated levels of GTP-bound N-RAS (N-RAS.GTP) in two human colorectal cancer cell lines, HCT 116 and DLD-1, compared to their isogenic counterparts in which the mutant KRAS allele has been disrupted by homologous recombination. N-RAS subserves an antiapoptotic role in cells expressing wild-type K-RAS; this function is compromised, however, by the presence of mutant K-RAS, and these cells display increased sensitivity to apoptotic stimuli. We additionally identify a physical interaction between N-RAS and gelsolin, a factor that has been shown to promote survival and show that the N-RAS:gelsolin complex is modulated differently in wild-type and mutant K-RAS environments following apoptotic challenge. These findings represent the first biochemical evidence of a functional relationship between endogenous RAS proteins and identify a dynamic physical interaction between endogenous N-RAS and gelsolin that correlates with survival.
Keller
J W
JW
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Haigis
K M
KM
Franklin
J L
JL
Whitehead
R H
RH
Jacks
T
T
Coffey
R J
RJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000502:physiology; D018938:Caco-2 Cells; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018260:Gelsolin / Q000378:metabolism* / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018260:Gelsolin; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins