The insulin-like growth factor (IGF) signaling system is a major arena of intragenomic conflict over embryonic growth between imprinted genes of maternal and paternal origin and the IGF type 1 receptor (IGF1R) promotes proliferation of many human cancers. The 3′-untranslated region (3′-UTR) of the mouse Igf1r mRNA is targeted by miR-675-3p derived from the imprinted H19 long noncoding RNA. Harvard University researchers undertook a comparative sequence analysis of vertebrate IGF1R 3′-UTRs to determine the evolutionary history of miR-675 target sequences and to identify conserved features that are likely to be involved in post-transcriptional regulation of IGF1R translation.
Sequences of IGF1R 3′-UTRs were obtained from public databases and analyzed using publicly available algorithms. A very long 3′-UTR is a conserved feature of vertebrate IGF1R mRNAs. The researchers found that some ancient microRNAs, such as let-7 and mir-182, have predicted binding sites that are conserved between cartilaginous fish and mammals. One very conserved region is targeted by multiple, maternally expressed imprinted microRNAs that appear to have evolved more recently than the targeted sequences.
(a) Phylogenetic relationships of species whose IGF1R 3′-UTRs are used in this study. The origin of genomic imprinting and the H19 long noncoding RNA is thought to coincide with stratum 3 (in an ancestor of marsupial and eutherian mammals). (b) Landmarks on the 7-kb 3′-UTR of the human ‘long’ IGF1R mRNA including conserved let-7-5p and miR-182 target sites. The 1.3 kb 3′-UTR of the ‘short’ transcript terminates within the VCR, which also includes a conserved miR-675-3p-binding site. The 0.8-kb megaloop is formed by pairing of the megaloop stems (MLS). The 4.8-kb gigaloop is a putative structure formed by pairing of VCR and a complementary sequence (cVCR)
The conserved structures that were identified in the IGF1R 3′-UTR are strong candidates for regulating cell proliferation during development and carcinogenesis. These conserved structures are now targeted by multiple imprinted microRNAs. These observations emphasize the central importance of IGF signaling pathways in the mediation of intragenomic conflicts over embryonic growth and identify possible targets for therapeutic interventions in cancer.