Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate diverse biological processes by controlling the pattern of expressed proteins. In mammalian cells, miRNAs partially complement their target sequences leading to mRNA degradation and/or decreased mRNA translation. Here, we have analyzed transcriptome-wide changes in miRNAs in senescent relative to early-passage WI-38 human diploid fibroblasts (HDFs). Among the miRNAs downregulated with senescence were members of the let-7 family, while upregulated miRNAs included miR-1204, miR-663 and miR-519. miR-519 was recently found to reduce tumor growth at least in part by lowering the abundance of the RNA-binding protein HuR. Overexpression of miR-519a in either WI-38 or human cervical carcinoma HeLa cells triggered senescence, as measured by monitoring beta-galactosidase activity and other senescence markers. These data suggest that miR-519 can suppress tumor growth by triggering senescence and that miR-519 elicits these actions by repressing HuR expression.
Highlights
IntroductionMicroRNAs are short (~ 22-nt) RNA molecules that modulate changes in gene expression [1,2]
MicroRNAs are short (~ 22-nt) RNA molecules that modulate changes in gene expression [1,2]. They are generated from precursor transcripts which are exported to the cytoplasm and are cleaved by Dicer; mature miRNAs assemble into ribonucleoprotein silencing complexes (RISC) that are recruited to specific mRNAs [3]
To test how the pattern of expressed microRNAs is affected by replicative senescence, we studied transcriptome-wide changes in microRNAs using miRNome arrays; we validated individual microRNAs by reverse transcription (RT) followed by real-time, quantitative (q)PCR amplification
Summary
MicroRNAs are short (~ 22-nt) RNA molecules that modulate changes in gene expression [1,2] They are generated from precursor transcripts (primary microRNAs) which are exported to the cytoplasm and are cleaved by Dicer; mature miRNAs assemble into ribonucleoprotein silencing complexes (RISC) that are recruited to specific mRNAs [3]. MicroRNAs function primarily as repressors of mRNA stability and translation [4] Through their influence on the patterns of expressed genes, microRNAs have been implicated in numerous physiologic processes, such as development of the muscular, immune, neuronal, epithelial and other systems, and in pathologies including neurodegeneration and cancer [5,6,7,8]. MiRNA-146a and miR-146b are upregulated in senescent cells and modulate inflammatory responses by suppressing secretion of IL-6 and IL-8 and by downregulating IRAK1 [15]
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