Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis |
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Authors: | Patek Charles E Arends Mark J Wallace William A H Luo Feijun Hagan Suzanne Brownstein David G Rose Lorraine Devenney Paul S Walker Marion Plowman Sarah J Berry Rachel L Kolch Walter Sansom Owen J Harrison David J Hooper Martin L |
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Affiliation: | a Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK b Department of Pathology, The University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK c Lothian Health University Hospitals Division & Division of Pathology, The University of Edinburgh, New Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK d The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK e Research Animal Pathology Core Laboratory, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK |
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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-rastmΔ4A/− 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-rastmΔ4A/tmΔ4A 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-rastmΔ4A/tmΔ4A 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-rastmΔ4A/− 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. |
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Keywords: | K-ras 4A K-ras 4B Lung cancer N-methyl-N-nitrosourea Mutation Erk, Akt |
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