Abstract
BackgroundCellular senescence is a specialized form of growth arrest that is generally irreversible. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1γ, HMGA, and DNMT proteins to produce a repressive chromatin environment. Therefore, senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging.Methodology/Principal FindingsAn in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX). Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p<0.05) and overexpression of miR-375 suppressed the normal proliferation of K562 cells. Upregulated miR-375 expression was associated with downregulated expression of 14-3-3zeta and SP1 genes. Autophagy was also investigated since DOX treatment was able to induce cells entering senescence and eventually lead to cell death. Among the 24 human autophagy-related genes examined, a 12-fold increase of ATG9B at day 4 and a 20-fold increase of ATG18 at day 2 after DOX treatment were noted.Conclusions/SignificanceThis study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation. The anti-proliferative function of miR-375 is possibly exerted, at least in part, by targeting 14-3-3zeta and SP1 genes.
Highlights
Cellular senescence is a specialized form of terminal differentiation that it is generally irreversible and is associated with characteristic alterations in morphology, physiology, gene expression [1,2,3,4], a typical upregulated senescence-associated-b-galactosidase (SA-b-gal) activity [5], and novel changes in chromatin architecture, i.e. the formation of senescence-associated heterochromatic foci (SAHF) [6]
It is believed that cellular senescence played a role in tumor suppression and aging [6] since the accumulation of senescent cells, the disturbance of the microenvironment, and the resulted compromised tissue function were often observed in age-related pathologies [6,7]
DOX Induced Senescence in K562 Cells To establish an in vitro cellular senescence model, K562 cells were treated with 50 nM of DOX
Summary
Cellular senescence is a specialized form of terminal differentiation that it is generally irreversible and is associated with characteristic alterations in morphology, physiology, gene expression [1,2,3,4], a typical upregulated senescence-associated-b-galactosidase (SA-b-gal) activity [5], and novel changes in chromatin architecture, i.e. the formation of senescence-associated heterochromatic foci (SAHF) [6]. MiRNAs have been implicated in cellular senescence and organismal aging since changes in miRNA expression levels and their putative targets were observed [20,21,22,23,24]. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1c, HMGA, and DNMT proteins to produce a repressive chromatin environment. Senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging
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