title: While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable.
abstract: In mammals, the three classical ras genes encode four highly homologous proteins, N-Ras, H-Ras, and the isoforms K-Ras 4A and 4B. Previous studies have shown that K-ras is essential for mouse development and that while K-ras 4A and 4B are expressed during development, K-ras 4A expression is regulated temporally and spatially and occurs in adult kidney, intestine, stomach, and liver. In the present study, the pattern of K-ras 4A expression was examined in a wide range of wild-type adult mouse tissues, and gene targeting was used to generate K-ras 4A-deficient mice to examine its role in development. It was found that K-ras 4A is also expressed in uterus, lung, pancreas, salivary glands, seminal vesicles, bone marrow cells, and cecum, where it was the major K-Ras isoform expressed. Mating between K-ras(tmDelta4A/+) mice produced viable K-ras(tmDelta4A/tmDelta4A) offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-ras(tmDelta4A/tmDelta4A) mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola x C57BL/6) genetic backgrounds. The results demonstrate that K-Ras 4A, like H- and N-Ras, is dispensable for normal mouse development, at least in the presence of functional K-Ras 4B.
authors.affiliation: Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, U.K.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Plowman
authors.forename: D James
authors.initials: DJ
authors.lastname: Williamson
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: O'Sullivan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Doig
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Ritchie
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.forename: David W
authors.initials: DW
authors.lastname: Melton
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hooper
authors.forename: Charles E
authors.initials: CE
authors.lastname: Patek
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D011905:Genes, ras; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics; D014018:Tissue Distribution
chemical_list: D020033:Protein Isoforms; D004247:DNA