miRNAs are largely known to base pair with the 3′UTR of target mRNAs, downregulating their stability and translation. mRNA of βTrCP1 ubiquitin ligase is very unstable, but unlike the majority of mRNAs where 3′UTR determines the rate of mRNA turnover, βTrCP1 mRNA contains cis-acting destabilizing elements within its coding region. Here we show that degradation of mRNA of βTrCP1 is miRNA dependent and identify miR-183 as a microRNA that interacts with the coding region of βTrCP1 mRNA. Argonaute2 interacts with the same region of βTrCP1 mRNA in an miR-183-dependent manner. Inhibition of miR-183 function or disruption of the miR-183-binding site stabilizes βTrCP1 mRNA and elevates βTrCP1 levels, resulting in activation of the SCFβTrCP E3 ubiquitin ligase. We previously showed that the RNA-binding protein CRD-BP binds to the coding region of βTrCP1 mRNA and stabilizes it. Here we demonstrate that CRD-BP prevents degradation of βTrCP1 mRNA by attenuating its miR-183-dependent interaction with Ago2.
Bibliographical noteFunding Information:
We thank Drs. K. Kinzler, P. Sharp, J. Ross, T. Tuschl, and B. Vogelstein for their generous gifts of reagents, Dr. S. Fuchs for critical reading of the manuscript, and Dr. K. Spiegelman and Mrs. I. Larsen for help with manuscript preparation. This work was supported by NCI grant CA121851 (to V.S.S.).