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The let-7 microRNA Family Regulates RAS: Implications for Development and Oncogenesis

contained at least one let-7 complementary sequence (LCS) [1, 5]. Among the identified genes, let-60/RAS stood out because it has eight LCSs and ten nonconforming sites in the 3' untranslated region (3'UTR), as well as three LCSs in the coding sequence. The role of let-60/RAS in C. elegans vulval development is well characterized [6], and expression studies showed that temporal regulation of let-60/RAS by let-7 miRNA at least partially accounts for the role of let-7 in seam and vulval cell differentiation [1]. Using genetic approaches and reporter constructs with the let-60/RAS 3'UTR, Johnson et al. also showed that the expression of let-60/RAS is regulated by two let-7 miRNA family members (let-7 and miR-84) via the 3'UTR of the let-60/RAS gene.


Human let-7 and RAS

let-60/RAS is the C. elegans orthologue of the human RAS genes, HRAS, KRAS, and NRAS. All three human RAS 3'UTRs contain multiple putative let-7 complementary sites with features of validated C. elegans LCSs. Many of the LCSs are conserved in rodents, amphibians, and fish, suggesting functional relevance. The presence of putative LCSs in human RAS 3'UTRs suggests that mammalian let-7 family members may regulate human RAS in a manner similar to the way let-7 and miR-84 regulate let-60/RAS in
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