Accumulating evidence indicates that hyperactive Wnt signalling occurs in association with the development and progression of human breast cancer. As a consequence of engaging the canonical Wnt pathway, a beta-catenin-T-cell factor (TCF) transcriptional complex is generated, which has been postulated to trigger the epithelial-mesenchymal transition (EMT) that characterizes the tissue-invasive phenotype. However, the molecular mechanisms by which the beta-catenin-TCF complex induces EMT-like programmes remain undefined. Here, we demonstrate that canonical Wnt signalling engages tumour cell dedifferentiation and tissue-invasive activity through an Axin2-dependent pathway that stabilizes the Snail1 zinc-transcription factor, a key regulator of normal and neoplastic EMT programmes. Axin2 regulates EMT by acting as a nucleocytoplasmic chaperone for GSK3beta, the dominant kinase responsible for controlling Snail1 protein turnover and activity. As dysregulated Wnt signalling marks a diverse array of cancerous tissue types, the identification of a beta-catenin-TCF-regulated Axin2-GSK3beta-Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.

This study describes the features of LRTIs associated with newly identified viruses in children, compared with those associated with known viruses. Additional investigations are required to define the role of HBoV in LRTI.

MicroRNAs (miRNAs) are known to post-transcriptionally regulate target mRNAs through the 39-UTR, which interacts mainly with the 59-end of miRNA in animals. Here we identify many endogenous motifs within human 59-UTRs specific to the 39-ends of miRNAs. The 39-end of conserved miRNAs in particular has significant interaction sites in the humanenriched, less conserved 59-UTR miRNA motifs, while human-specific miRNAs have significant interaction sites only in the conserved 59-UTR motifs, implying both miRNA and 59-UTR are actively evolving in response to each other. Additionally, many miRNAs with their 39-end interaction sites in the 59-UTRs turn out to simultaneously contain 59-end interaction sites in the 39-UTRs. Based on these findings we demonstrate combinatory interactions between a single miRNA and both end regions of an mRNA using model systems. We further show that genes exhibiting large-scale protein changes due to miRNA overexpression or deletion contain both UTR interaction sites predicted. We provide the predicted targets of this new miRNA target class, miBridge, as an efficient way to screen potential targets, especially for nonconserved miRNAs, since the target search space is reduced by an order of magnitude compared with the 39-UTR alone. Efficacy is confirmed by showing SEC24D regulation with hsa-miR-605, a miRNA identified only in primate, opening the door to the study of nonconserved miRNAs. Finally, miRNAs (and associated proteins) involved in this new targeting class may prevent 40S ribosome scanning through the 59-UTR and keep it from reaching the start-codon, preventing 60S association.

No abstract