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oai:repisalud.isciii.es:20.500.12105/147032024-11-29T15:11:55Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Salmón, Marina author Paniagua, Guillem author Fernández-García, Fernando author Zarzuela, Eduardo author Álvarez-Díaz, Ruth author Musteanu, Mónica author Muñoz, Javier author Drosten, Matthias author Lechuga, Carmen G author Guerra, Carmen author Caleiras, E author Ortega Jimenez, Sagrario author Barbacid, Mariano author 2021-07-27 In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a Kras FSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras +/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras +/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences. Proc Natl Acad Sci U S A . 2021;118(30):e2023112118. 10.1073/pnas.2023112118 1091-6490 Proceedings of the National Academy of Sciences of the United States of America 34301865 http://hdl.handle.net/20.500.12105/14703 K-RAS 4A SPLICE VARIANT H-RAS MOUSE SPECIFICITY ONCOGENES CANCER 4B KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.