The microRNA-30e as a decision maker in stress-induced signaling pathways

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Based on their capability to post-transcriptionally modulate expression of a large portion of the proteome, small (19-23 nucleotides) non-coding RNA molecules, so-called microRNAs (miRs), play a central role in diverse cellular processes. As miRs are able to target numerous mRNAs, that up to now remain largely unknown, we are far from fully understanding specific functions of individual miRs. By means of microarray analyses we identified besides the well-known p53 target miR-34a also several other miRs including miR-30c and miR-30e that were induced by ionizing irradiation in a p53-dependent manner. Although the five members of the miR-30 family contain an identical seed sequence and thus should recognize similar target mRNAs, only ectopic expression of miR-30e, but not of miR-30c rescues tumor cells from apoptosis induced by ionizing irradiation, etoposide or overexpression of miR-34a. Interestingly, miR-30e was not only able to protect the cells from stress-induced apoptosis, but in addition, induced a strong and permanent cell cycle arrest called senescence. Consistent with these processes, miR-30e was found to modulate expression of caspase-3 and the cyclin-dependent kinase inhibitior p21. Following an in-depth analysis of these issues, we will then closely examine not only the putative p53 dependency of miR-30e expression, but conversely investigate their impact on p53-dependent and -independent stress-induced signaling pathways. Using various bioinformatical and experimental approaches, we will identify additional miR-30e targets that like p21 will be thoroughly investigated with regard to their influence on miR-30e-regulated stress responses.