Rare codons capacitate Kras-driven de novo tumorigenesis
Nicole L.K. Pershing, … , David M. MacAlpine, Christopher M. Counter
Nicole L.K. Pershing, … , David M. MacAlpine, Christopher M. Counter
Published December 1, 2014
Citation Information: J Clin Invest. 2015;125(1):222-233. https://doi.org/10.1172/JCI77627.
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Research Article Oncology

Rare codons capacitate Kras-driven de novo tumorigenesis

Abstract

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

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Figure 4

Detection of fewer and different mutations in the Krasex3op allele from tumors of mice treated with urethane.

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Detection of fewer and different mutations in the Krasex3op allele from ...
(A) Amplification strategy for Kras RT-PCR including location of SNPs used for strain identification. Green arrows indicate primers for Sanger sequencing; blue arrows indicate primers for Ion Torrent sequencing. (B and C) Sequencing by the (B) Sanger and (C) Ion Torrent methods of Kras cDNAs from the indicated number (n) of tumors arising in the indicated urethane-treated cohorts revealed fewer and different mutations in the Krasex3op allele. Pie charts are sized to reflect differences in overall tumor multiplicity for each genotype.