| First Author | Salmón M | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 30 | PubMed ID | 34301865 |
| Mgi Jnum | J:308301 | Mgi Id | MGI:6729128 |
| Doi | 10.1073/pnas.2023112118 | Citation | Salmon M, et al. (2021) KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform. Proc Natl Acad Sci U S A 118(30):e2023112118 |
| abstractText | 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 KRAS4B(154) 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 KRAS4A(G12V) 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 KRAS4A(G12V) mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4B(G12V) oncoprotein may not have significant therapeutic consequences. |
