MicroRNAs and senescence

discovery and analysis of microRNAs (miRNAs) has revealed a new mechanism of gene regulation. miRNAs can base-pair with specific mRNA targets and regulate their expression at the post-transcriptional level [1]. Changes in miRNA abundance are implicated in controlling many biological processes including cellular senescence [2], an irreversible form of growth arrest involved in cellular aging. The p53 and retinoblastoma (Rb) tumor suppressor pathways are essential for the establishment and maintenance of growth arrest during senescence [3], reflecting the need of cells to bypass senescence during carcinogenesis. Multiple miRNAs have been implicated in regulating the p53 pathway during cellular senescence. For example, miR-217 and the miR-34 family target the SIRT1 deacetylase gene. Reduction of SIRT1 expression by these miRNAs permits the maintenance of p53 acetylation, resulting in p53 stabilization and the induction of senescence [4, 5]. In mouse embryonic fibroblasts, miR-20a represses the expression of the transcriptional regulator LRF (Leukemia/Lymphoma Related Factor), a repressor of the p19ARF gene. The absence of LRF increases the expression of p19ARF, which in turn inhibits the expression of the ubiquitin ligase MDM2, causing up-regulation of p53 and induction of senescence [6]. Our group determined which miRNAs were differentially expressed during Rb-induced senescence, and we explored the roles of some of these miRNAs in this process [7]. We analyzed the global expression of miRNAs in an established model of cellular senescence in which repression of the human papillomavirus E7 Commentary oncogene causes the rapid induction of Rb-dependent senescence in HeLa cervical carcinoma cells [8,9]. We found that 25 miRNAs were up-regulated and 24 were down-regulated in an Rb-dependent manner during induced senescence. Notably, several members of the miR-29 and miR-30 families were up-regulated during senescence, and this up-regulation required activation of the Rb pathway. Further analysis showed that miR-29 and miR-30 target the 3' untranslated region (3'UTR) of B-Myb mRNA [7]. The B-Myb oncogene (also known as MYBL2) encodes a transcription factor that regulates genes involved in control of the cell cycle, and modulation of B-Myb expression is known to influence senescence [10,11,12]. The interaction of miR-29 and miR-30 with the B-Myb 3'UTR inhibits gene expression during both induced and replicative senescence. B-Myb expression can also be repressed by direct binding of Rb-E2F factors to the B-Myb promoter. Interestingly, over-expression of miR-29 and miR-30 in proliferating cells suppresses B-Myb expression and cellular DNA synthesis, and inhibiting the expression of these miRNAs allowed a population of cells …