p21(Waf1) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate
| Autor: | Valery A. Pospelov, Vasily S. Romanov, Svetlana G. Zubova, S. B. Svetlikova, Albert J. Fornace, Tatiana V. Pospelova, Bykova Tv, Abramova Mv, Nikolai D. Aksenov |
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| Rok vydání: | 2010 |
| Předmět: |
Senescence
Cyclin-Dependent Kinase Inhibitor p21 Cell cycle checkpoint Biology Oncogene Protein p21(ras) Cell Line Focal adhesion chemistry.chemical_compound Mice Animals Molecular Biology Cells Cultured Cellular Senescence Mice Knockout TOR Serine-Threonine Kinases Cell Cycle Sodium butyrate Cell migration Cell Biology Cell cycle Fibroblasts Cell biology Histone Deacetylase Inhibitors Butyrates chemistry Cell culture Cell aging Biomarkers Developmental Biology |
| Zdroj: | Cell cycle (Georgetown, Tex.). 9(19) |
| ISSN: | 1551-4005 |
| Popis: | Cell senescence is characterized by senescent morphology and permanent loss of proliferative potential. HDAC inhibitors (HDACI) induce senescence and/or apoptosis in many types of tumor cells. Here, we studied the role of cyclin-kinase inhibitor p21(waf1) (Cdkn1n gene) in cell cycle arrest, senescence markers (cell hypertrophy, SA-βGal staining and accumulation of γH2AX foci) in p21(Waf1+/+) versus p21(Waf1-/-) mouse embryonic fibroblast cells transformed with E1A and cHa-Ras oncogenes (mERas). While short treatment with the HDACI sodium butyrate (NaB) induced a reversible G(1) cell cycle arrest in both parental and p21(Waf1-/-) cells, long-term treatment led to dramatic changes in p21(Waf1+/+) cells only: cell cycle arrest became irreversible and cells become hypertrophic, SA-βGal-positive and accumulated γH2AX foci associated with mTORC1 activation. The p21(Waf1+/+) cells lost their ability to migrate into the wound and through a porous membrane. Suppression of migration was accompanied by accumulation of vinculin-staining focal adhesions and Ser3-phosphorylation of cofilin, incapable for F-actin depolymerization. In contrast, the knockout of the p21(Waf1) abolished most of the features of NaB-induced senescence, including irreversibility of cell cycle arrest, hypertrophy, additional focal adhesions and block of migration, γH2AX foci accumulation and SA-βGal staining. Rapamycin, a specific inhibitor of mTORC1 kinase, decreased cellular hypertrophy, canceled coffilin phosphorylation and partially restored cell migration in p21(Waf1+/+) cells. Taken together, our data indicate a new role of p21(Waf1) in cell senescence, which may be connected not only with execution of cell cycle arrest, but also with the development of mTOR-dependent markers of cellular senescence. |
| Databáze: | OpenAIRE |
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