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.
Patek
Charles E
CE
Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Arends
Mark J
MJ
Wallace
William A H
WA
Luo
Feijun
F
Hagan
Suzanne
S
Brownstein
David G
DG
Rose
Lorraine
L
Devenney
Paul S
PS
Walker
Marion
M
Plowman
Sarah J
SJ
Berry
Rachel L
RL
Kolch
Walter
W
Sansom
Owen J
OJ
Harrison
David J
DJ
Hooper
Martin L
ML
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