Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis.
To examine the roles of endogenous K-ras 4A and K-ras 4B splice variants in tumorigenesis, murine lung carcinogenesis was induced by N-methyl-N-nitrosourea (MNU), which causes a K-ras mutation (G12D) that jointly affects both isoforms. Compared with age-matched K-ras(tmDelta4A/-) mice (where tumours can express mutationally activated K-ras 4B only), tumour number and size were significantly higher in K-ras(+/-) mice (where tumours can also express mutationally activated K-ras 4A), and significantly lower in K-ras(tmDelta4A/tmDelta4A) mice (where tumours can express both wild-type and activated K-ras 4B). MNU induced significantly more, and larger, tumours in wild-type than K-ras(tmDelta4A/tmDelta4A) mice which differ in that only tumours in wild-type mice can express wild-type and activated K-ras 4A. Lung tumours in all genotypes were predominantly papillary adenomas, and tumours from K-ras(+/-) and K-ras(tmDelta4A/-) mice exhibited phospho-Erk1/2 and phospho-Akt staining. Hence (1) mutationally activated K-ras 4B is sufficient to activate the Raf/MEK/ERK(MAPK) and PI3-K/Akt pathways, and initiate lung tumorigenesis, (2) when expressed with activated K-ras 4B, mutationally activated K-ras 4A further promotes lung tumour formation and growth (both in the presence and absence of its wild-type isoform) but does not affect either tumour pathology or progression, and (3) wild-type K-ras 4B, either directly or indirectly, reduces tumour number and size.
Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Charles E
CE
Patek
Mark J
MJ
Arends
William A H
WA
Wallace
Feijun
F
Luo
Suzanne
S
Hagan
David G
DG
Brownstein
Lorraine
L
Rose
Paul S
PS
Devenney
Marion
M
Walker
Sarah J
SJ
Plowman
Rachel L
RL
Berry
Walter
W
Kolch
Owen J
OJ
Sansom
David J
DJ
Harrison
Martin L
ML
Hooper
D000818:Animals; D018450:Disease Progression; D008175:Lung Neoplasms / Q000209:etiology* / Q000473:pathology; D008770:Methylnitrosourea; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis / Q000235:genetics; D050505:Mutant Proteins; D020033:Protein Isoforms; D015398:Signal Transduction; D047368:Tumor Burden / Q000235:genetics; D018631:ras Proteins / Q000235:genetics* / Q000502:physiology
D050505:Mutant Proteins; D020033:Protein Isoforms; D008770:Methylnitrosourea; D018631:ras Proteins