Cell cycle control of microRNA-mediated translation regulation

Abstract

MicroRNAs are small regulatory RNA molecules that exert post-transcriptional control over expression of specific target mRNAs. AU-rich elements (AREs) are highly conserved 3′UTR sequences that alter the stability and translation of mRNAs of clinical importance as a rapid and transient response to external and internal changes. We recently demonstrated that a reporter mRNA containing the tumor necrosis factor α (TNFα) ARE activates translation in response to quiescence via microRNA target sites in the ARE. Further studies revealed that microRNAs in general have the potential to regulate translation in a cell-cycle determined manner: in quiescent cells, microRNAs activate translation while in cycling/proliferating cells, microRNAs repress translation.

In this study, we have analyzed microRNA regulation of translation at additional stages of the cell cycle. We observe the strongest repressive potential in the S and S/G2 phases with minimal repression in the G1 phase. Since asynchronously growing cells are predominantly in G1, these data may explain the variable magnitude of microRNA-mediated repression reported in the literature. Importantly, we observe activation in contact-inhibited G0 quiescent cells, reaffirming that the quiescent state and not serum-starvation-induced stress causes microRNA-mediated translation upregulation. In addition, we find that siRNPs, unlike microRNPs, downregulate expression of a reporter in serum-starvation-induced G0 arrested cells, as well as in proliferating cells. Our data underscore the importance of the quiescent state for microRNA-mediated translation activation and suggest the potential for further novel functions of microRNAs in distinct cell fates.