Antagonistic interactions between microRNAs underlie robust tumor suppressor responses.
- Author(s): Sabio, Erich Yanson
- Advisor(s): He, Lin
- et al.
The oncogenic mir-17-92 cluster encodes six coordinately expressed miRNAs with a unique capacity for gene regulation. In this dissertation, we have extended our studies of the mir-17-92 cluster in order to explore two fundamental concepts: functional consequences of aberrant miRNA expression, and distinct regulation within a miRNA polycistron. In the Eμ-myc Burkitt’s lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Here we report that, surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. The effect of miR-92 is mediated, in part, through direct repression of Fbw7 which normally promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to c-Myc-induced proliferation strongly coupled to p53-dependent apoptosis. Ultimately, we reveal an antagonistic interaction between miR-19 and miR-92 that is disrupted in B-lymphoma cells, which favor a greater increase for miR-19 than miR-92. Furthermore, we have identified an RBP, Hnrnpu, as a factor that is bound to miR-19b, transcriptionally regulated by Myc, overexpressed in Burkitt’s Lymphoma, required for maintining miR-19b abundance, and therefore a plausible candidates for trans-acting factors that alter the ratio of miR-19:miR-92. These studies add to our understanding of how individual miRNAs within a single cluster may act as antagonists, as well as how these antagonistic interactions are regulated.