Rare Codons Regulate KRas Oncogenesis

SummaryOncogenic mutations in the small Ras GTPases KRas, HRas, and NRas render the proteins constitutively GTP bound and active, a state that promotes cancer [1]. Ras proteins share ∼85% amino acid identity [2], are activated by [3] and signal through [4] the same proteins, and can exhibit functional redundancy [5 and 6]. Nevertheless, manipulating expression or activation of each isoform yields different cellular responses [7, 8, 9 and 10] and tumorigenic phenotypes [11, 12 and 13], even when different ras genes are expressed from the same locus [ 6]. We now report a novel regulatory mechanism hardwired into the very sequence of RAS genes that underlies how such similar proteins impact tumorigenesis differently. Specifically, despite their high sequence similarity, KRAS is poorly translated compared to HRAS due to enrichment in genomically underrepresented or rare codons. Converting rare to common codons increases KRas expression and tumorigenicity to mirror that of HRas. Furthermore, in a genome-wide survey, similar gene pairs with opposing codon bias were identified that not only manifest dichotomous protein expression but also are enriched in key signaling protein classes and pathways. Thus, synonymous nucleotide differences affecting codon usage account for differences between HRas and KRas expression and function and may represent a broader regulation strategy in cell signaling.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (169 K)Download as PowerPoint slideHighlights► Mammalian KRAS is enriched in rare codons that limit its expression ► Changing rare to common codons increases ectopic and endogenous KRAS expression ► KRAS oncogenicity is limited by rare codons ► Other gene pairs exhibit high sequence identity but opposing codon bias