p21(Waf1) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate
Romanov, VS; Abramova, MV; Svetlikova, SB; Bykova, TV; Zubova, SG; Aksenov, ND; Fornace, AJ, Jr; Pospelova, TV; Pospelov, VA
| HERO ID | 1458346 |
|---|---|
| In Press | No |
| Year | 2010 |
| Title | p21(Waf1) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate |
| Authors | Romanov, VS; Abramova, MV; Svetlikova, SB; Bykova, TV; Zubova, SG; Aksenov, ND; Fornace, AJ, Jr; Pospelova, TV; Pospelov, VA |
| Journal | Cell Cycle |
| Volume | 9 |
| Issue | 19 |
| Page Numbers | 3945-3955 |
| Abstract | 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-beta Gal staining and accumulation of gamma H2AX 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-beta Gal-positive and accumulated gamma H2AX 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 gamma H2AX foci accumulation and SA-beta Gal 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. |
| Doi | 10.4161/cc.9.19.13160 |
| Pmid | 20935470 |
| Wosid | WOS:000282703600025 |
| Url | http://www.landesbioscience.com/journals/cc/article/13160/ |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Source: Web of Science WOS:000282703600025 |
| Is Public | Yes |
| Keyword | HDAC inhibitors; p21(Waf1); cell cycle arrest; cell hypertrophy; motility |