Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis

Charles E. Patek, Mark Arends, William Wallace, Feijun Luo, Suzanne Hagan, David G. Brownstein, Lorraine Rose, Paul S. Devenney, Marion Walker, Sarah Plowman, Rachel L. Berry, Walter Kolch, Owen J. Sansom, David J. Harrison, Martin L. Hooper

Research output: Contribution to journalArticlepeer-review

Abstract

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(tmA4A/-) 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-TaStm Delta 4A/tm Delta 4A 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(tm Delta 4A/tm Delta 4A) 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(tm Delta 4A/-) 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 P13-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. (c) 2007 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)1105-1114
Number of pages10
JournalExperimental Cell Research
Volume314
Issue number5
DOIs
Publication statusPublished - 10 Mar 2008

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