Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts
Cellular senescence can result from short, dysfunctional telomeres, oxidative stress, or oncogene expression, and may contribute to aging. To investigate the role of cellular senescence in aging it is necessary to define the time-dependent molecular events by which it is characterized. Here we inves...
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Veröffentlicht in: | The Journal of biological chemistry 2004-11, Vol.279 (47), p.49439-49446 |
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Sprache: | eng |
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Zusammenfassung: | Cellular senescence can result from short, dysfunctional telomeres, oxidative stress, or oncogene expression, and may contribute
to aging. To investigate the role of cellular senescence in aging it is necessary to define the time-dependent molecular events
by which it is characterized. Here we investigated changes in levels of key proteins involved in cell cycle regulation, DNA
replication, and stress resistance in senescing human fibroblasts following oxidative stress. An immediate response in stressed
cells was dephosphorylation of retinoblastoma (Rb) and cessation of DNA synthesis. This was followed by sequential induction
of p53, p21, and p16. Increase in hypophosphorylated Rb and induction of p53 and p21 by a single stress treatment was transient,
whereas sustained induction or dephosphorylation were achieved by a second stress. Down-regulation of the critical DNA replication
initiation factor Cdc6 occurred early after stress concurring with p53 induction, and was followed by a decrease in Mcm2 levels.
A late event in the stress-induced molecular sequence was the induction of SOD1, catalase, and HSP27 coinciding with development
of the fully senescent phenotype. Our data suggest that loss of proliferative capacity in oxidatively stressed cells is a
multistep process regulated by time-dependent molecular events that may play differential roles in induction and maintenance
of cellular senescence. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M409153200 |