Figure 6

Speculated role of miR-23a~27a~24-2 cluster in regulation of Wnt Signaling. In normal circumstances, β-catenin protein is under the inhibitory effect of GSK-3β which leads to its degradation but when the Wnt signaling proteins bind to its receptors Frizzled and LRP-5 and -6; it leads to the activation of disheveled protein. This protein inhibits GSK-3β, thus preventing the degradation of β-catenin. Once the β-catenin is stabilized, it translocates to the nucleus and regulates the gene expression. In the various pathological conditions where this cluster is over expressed as is the case in many cancerous tissues, the Wnt genes; WNT3A and WNT4 could be targeted by miR-27a and miR-24 respectively, LRP5 and LRP6 by miR-23a and miR-27a respectively and FZD4 and FZD7 are targeted by both miR-23a and miR-27a. This leads to the inactivation of DVL1 protein. Also, DVL1 could itself be down-regulated by miR-27a. As a result, GSK-3β causes degradation of β-catenin, thus preventing its translocation to the nucleus and ultimately the transcription. To conserve the cells energy resources β-catenin associated genes like Cyclin D (targeted by miR-23a) and TCF7 (targeted by miR-24) are also inhibited. Among the other inhibitors of β-catenin (APC, Axin and PP2A), APC is targeted by miR-23a and PP2A by miR-27a, maybe these inhibitors are not required once GSK-3β is there to degrade β-catenin.