Cancer pathogenesis is based on the abnormal proliferation of cells. MicroRNAs (miRNAs) are small RNA molecules regulating gene expression by targeting mRNAs for translational repression and/or degradation and are involved in human oncogenesis. Recent studies show translational repression by miRNAs is influenced by cellular proliferation states. To further progress the basic understanding of miRNA-mediated gene regulation and reveal the affects of abnormal cellular proliferation on miRNA-regulation, transgenic mice will be engineered with a bioluminescent reporter transgene targeted for miRNA regulation. The in vivo miRNAs translational repression levels will be quantified in different cellular proliferative states and correlated to stable miRNA cellular concentration. Whole animal studies and tissue-specific quantification will be performed using non-invasive fluorescent microscopy and fluorometry. By crossing the miRNA reporter transgenic mouse with various cancer models for tumor and lymphoproliferative disorders, the affect of abnormal proliferation on miRNA regulation will be monitored to test how it may contribute to cancer progression. Public Health Relevance: MicroRNAs are small regulatory RNA molecules controlling gene expression and have been linked to cancer formation. To advance our understanding of microRNA regulation, we will develop a system for measuring miRNA-mediated translational repression in normal and diseased tissue. The goals are to gain insight into in vivo miRNA regulation and measure the contribution of abnormal growth in progressing cancer development through defective miRNA regulation.
| Zamudio, Jesse R; Kelly, Timothy J; Sharp, Phillip A (2014) Argonaute-bound small RNAs from promoter-proximal RNA polymerase II. Cell 156:920-34 |
| Bosson, Andrew D; Zamudio, Jesse R; Sharp, Phillip A (2014) Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol Cell 56:347-59 |
