The KRAS gene is commonly mutated in human cancers, rendering the encoded small GTPase constitutively active and oncogenic. This gene has the unusual feature of being enriched for rare codons, which limit protein expression. Here, to determine the effect of the rare codon bias of the KRAS gene on de novo tumorigenesis, we introduced synonymous mutations that converted rare codons into common codons in exon 3 of the Kras gene in mice. Compared with control animals, mice with at least 1 copy of this Krasex3op allele had fewer tumors following carcinogen exposure, and this allele was mutated less often, with weaker oncogenic mutations in these tumors. This reduction in tumorigenesis was attributable to higher expression of the Krasex3op allele, which induced growth arrest when oncogenic and exhibited tumor-suppressive activity when not mutated. Together, our data indicate that the inherent rare codon bias of KRAS plays an integral role in tumorigenesis.
Authors
Nicole L.K. Pershing, Benjamin L. Lampson, Jason A. Belsky, Erin Kaltenbrun, David M. MacAlpine, Christopher M. Counter
(A) Strategy to generate KrasLSL–G12D/ex3op and KrasLSL–G12D/nat littermates for analysis of tumor burden. (B and C) Reduction of tumor burden (mean ± SEM) in KrasLSL–G12D/ex3op versus KrasLSL–G12D/nat mice (B) 4 months (n ≥8) and (C) 6 months (n ≥9) after AdCre administration . *P > 0.05 by unpaired, 2-tailed t test.