Abstract
Long noncoding RNAs (lncRNAs) have gained extensive attentions in recent years because of their potential importance in a variety of biological and pathological processes. In this study, we sought to explore the role of lncRNAs in cellular senescence. Here, we report that the lncRNA AK156230 was downregulated during replicative senescence in mouse embryonic fibroblasts (MEFs), and knockdown of AK156230 promotes a robust senescence phenotype, including increase in the numbers of the senescence-associated β-galactosidase-positive cells, decrease of cell proliferation, accumulation of cells in the G2/M phase and reduction of autophagic activity. The cells with knockdown AK156230 expression also exhibited increased levels of p21, p53 and phosphorylated p53, and a decreased activity of CDK1. Moreover, rapamycin-induced autophagy offered cytoprotective effect and rescued cellular senescence in AK156230 knockdown cells. Gene expression profile showed that the dysregulation of autophagy and cell cycle genes contributed to the induction of cellular senescence after AK1561230 silencing. Taken together, these results suggest that downregulation of AK156230 is involved in the induction of cellular senescence through its roles in autophagy and cell cycle progression. Our study identifies AK156230 as a critical lncRNA that has a role in regulating cellular senescence in MEFs.
Highlights
Replicative senescence (RS) is a cellular state of irreversible growth arrest and loss of replicative capacity [1], and can be triggered by a variety of factors such as DNA damage, telomere shortening, oncogenic activation, or oxidative stresses [2, 3]
Great efforts have been made in understanding the expression patterns and functions of long noncoding RNAs (lncRNAs), and the importance of these non-coding RNAs has been increasingly appreciated [31,32,33]; yet, so far only a small portion of this class of non protein-coding transcripts are known to be involved in regulating cellular senescence, and those results were obtained in different types of human tissues and cells
It was reported that the lncRNAs, ASncmtRNA-2 and MIR31HG, were closely related to cellular senescence and aging process [35, 36]
Summary
Replicative senescence (RS) is a cellular state of irreversible growth arrest and loss of replicative capacity [1], and can be triggered by a variety of factors such as DNA damage, telomere shortening, oncogenic activation, or oxidative stresses [2, 3]. There has been an increasing appreciation of the roles of noncoding RNAs (ncRNAs) in regulating gene expression during cellular senescence [5, 13, 14]. This large class of noncoding RNAs comprise small www.impactjournals.com/oncotarget transcripts such as siRNAs and miRNAs, and a vast majority of long noncoding RNAs (lncRNAs) [15]. LncRNAs are currently defined as transcripts of greater than 200 nucleotides that lack the protein-coding capacity [16]. Increasing numbers of lncRNAs have been reported to be involved in cellular processes including proliferation, differentiation, survival or apoptosis, and a variety of human diseases such as neurodegeneration, cardiovascular disease, and cancer [21,22,23,24,25]
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