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

Patek, C. et al. (2008) Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis. Experimental Cell Research, 314(5), pp. 1105-1114. (doi:10.1016/j.yexcr.2007.11.004)

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Publisher's URL: http://dx.doi.org/10.1016/j.yexcr.2007.11.004

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Walker, Mr Mark and Hagan, Dr Suzanne and Kolch, Prof Walter and Sansom, Professor Owen
Authors: Patek, C., Arends, M., Wallace, W., Luo, F., Hagan, S., Brownstein, D., Rose, L., Devenny, P., Walker, M., Plowman, S., Berry, R., Kolch, W., Sansom, O., Harrison, D., and Hooper, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Experimental Cell Research
ISSN:00144827

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