Rare codons capacitate Kras-driven de novo tumorigenesis

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...

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Bibliographic Details
Published inThe Journal of clinical investigation Vol. 125; no. 1; pp. 222 - 233
Main Authors Pershing, Nicole L K, Lampson, Benjamin L, Belsky, Jason A, Kaltenbrun, Erin, MacAlpine, David M, Counter, Christopher M
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 01.01.2015
Subjects
Adenoma - chemically induced
Adenoma - genetics
Adenoma - pathology
Animals
Bias
Biomedical research
Cancer
Carcinogenesis
Carcinogenesis - genetics
Cell Proliferation
Cells, Cultured
Codon
Comparative analysis
Experiments
Female
Genes
Genetic aspects
Humans
Laboratories
Lung Neoplasms - chemically induced
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Male
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Physiological aspects
Protein expression
Proteins
Proto-Oncogene Proteins p21(ras) - genetics
Rodents
Software
Tumor Burden
Tumorigenesis
Urethane
United States
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Summary: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 Kras(ex3op) 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 Kras(ex3op) 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0021-9738
1558-8238
DOI:10.1172/JCI77627