Ki-ras and the characteristics of mouse lung tumors

Codon 12 mutations are frequent in the Ki-ras oncogene in human lung adenoc arcinomas, but the effects of these alterations have not been well characte rized in lung epithelial cells. Murine primary lung tumors derived from per ipheral epithelial cells also may present Ki-ras mutations and are useful m odels for study of early phases of tumor development. One hypothesis is tha t Ki-ras mutation and/or a Ki-ras p21 increase could enhance Ki-ras p21-GTP and cell-cycle stimulation through raf-1 and extracellularly regulated pro tein kinases (Erks). We examined lung tumors 1-7 mm in largest dimension in itiated in male Swiss mice by N-nitrosoldimethylamine for pathologic type, Ki-ras mutations and levels of total Ki-ras p21, Ki-ras p21 bound to GTP, r af-1, Erk1 and Erk2 and their phosphorylated (activated) forms; and prolife rating cell nuclear antigen. Total Ki-ras p21 and activated ras-GTP were no t significantly greater in tumors than in normal lung or in tumors with ver sus those without Ki-ras mutations. Carcinomas with Ki-ras mutations were s ignificantly smaller than those without mutations. Carcinomas were signific antly larger than adenomas only for tumors without mutations. High levels o f Erk1 and correlation of Erk2 amount with ras-GTP were specific characteri stics of tumors with Ki-ras mutations. Size of all tumors correlated with r as-GTP but not with proliferating cell nuclear antigen. Raf-1 was expressed mainly in alveolar macrophages in normal lung but was focally upregulated in papillary areas of some tumors. The results indicate that Ki-ras influen ces the characteristics of lung tumors, but a linear ras-raf-Erk-cell-cycle control sequence does not adequately characterize tumorigenic events in th is model. Published 2000 Wiley-Liss, Inc.(dagger).