In:
Aging Cell, Wiley, Vol. 12, No. 3 ( 2013-06), p. 446-458
Abstract:
Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo , their effect on their microenvironment and its double‐edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age‐associated diseases in mouse model systems. To characterize the role of mi RNA s in cellular senescence of endothelial cells, we performed mi RNA arrays from HUVEC s of five different donors. Twelve mi RNA s, comprising hsa‐mi R ‐23a, hsa‐mi R ‐23b, hsa‐mi R ‐24, hsa‐mi R ‐27a, hsa‐mi R ‐29a, hsa‐mi R ‐31, hsa‐mi R ‐100, hsa‐mi R ‐193a, hsa‐mi R ‐221, hsa‐mi R ‐222 and hsa‐let‐7i are consistently up‐regulated in replicatively senescent cells. Surprisingly, also miR‐21 was found up‐regulated by replicative and stress‐induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with mi R ‐21 resulted in lower angiogenesis, and less cell proliferation mirrored by up‐regulation of p21 CIP1 and down‐regulation of CDK 2. These two cell‐cycle regulators are indirectly regulated by mi R ‐21 via its validated direct targets NFIB (Nuclear factor 1 B ‐type), a transcriptional inhibitor of p21 CIP 1 , and CDC 25A, which regulates CDK 2 activity by dephosphorylation. Knock‐down of either NFIB or CDC 25A shows a phenocopy of over‐expressing miR‐21 in regard to cell‐cycle arrest. Finally, mi R ‐21 over‐epxression reduces the replicative lifespan, while stable knock‐down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that mi R ‐21 is the first mi RNA that upon its knock‐down extends the replicative lifespan of normal human cells.
Type of Medium:
Online Resource
ISSN:
1474-9718
,
1474-9726
DOI:
10.1111/acel.2013.12.issue-3
Language:
English
Publisher:
Wiley
Publication Date:
2013
detail.hit.zdb_id:
2099130-7
SSG:
12
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