| p21(Waf1) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate. | |
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MedLine Citation:
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PMID: 20935470 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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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. |
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Authors:
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V S Romanov; M V Abramova; S B Svetlikova; T V Bykova; S G Zubova; N D Aksenov; A J Fornace; T V Pospelova; V A Pospelov |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-26 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 9 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 3945-55 Citation Subset: IM |
Affiliation:
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Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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