Oncogenic ras induces premature senescence in endothelial cells: role of p21Cip1/Waf1

被引:0
作者
Ioakim Spyridopoulos
Jeffrey M. Isner
Douglas W. Losordo
机构
[1] Dept. of Cardiology and Cardiovascular Research,
[2] Medizinische Klinik III,undefined
[3] Otfried-Mueller-Str. 10,undefined
[4] 72076 Tübingen,undefined
[5] Germany,undefined
[6] E-Mail: ioakim_s@hotmail.com,undefined
[7] Tel.: +49-7071/2984482,undefined
[8] Fax: +49-7071/295019,undefined
[9] Dept. of Cardiovascular Research,undefined
[10] St. Elizabeths Medical Center,undefined
[11] 736 Cambridge St,undefined
[12] Boston,undefined
[13] MA 02135/USA,undefined
[14] E-Mail: dlorordo@opal.tufts.edu,undefined
[15] Tel.: +1-617/789-3346,undefined
[16] Fax: +1-617/789-5029,undefined
来源
Basic Research in Cardiology | 2002年 / 97卷
关键词
Key words Atherosclerosis – Ras – senescence – cell cycle – endothelial cells – p21 – apoptosis;
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摘要
Recent studies have shown that the presence of tumor suppressors such as p53 or p16 account for the lack of transformation in primary cells. To investigate a potential role of active Ras in atherosclerosis, we infected bovine aortic endothelial cells with a replication-deficient, recombinant adenovirus containing the activated H-Ras61L gene. Ras overexpression led after 72 hours to G1- and G2/M-cell cycle arrest due to induction of p21Cip1/Waf1. Treatment of Ras-infected endothelial cells with 40 ng/ml TNF-α for 20 hours augmented apoptosis 8-fold in comparison to Ad-Con (control virus with empty expression cassette) infected cells (36.2 % vs. 4.3 %, p < 0.001), while Ras itself did not cause any cell death. Furthermore, more than 58 % of Ras-infected cells stained positive for senescence-associated β-galactosidase activity as opposed to 2 % in control vector-infected cells (p < 0.001), strongly suggesting a senescent phenotype in the Ras-infected population. We found further features of senescence in Ras-transduced endothelial cells, such as growth arrest and the lack of AP-1 serum inducibility. Finally, we evaluated the role of p21Cip1/Waf1 in this process of senescence. Adenoviral overexpression of p21 led to growth arrest by induction of G1- and G2/M-cell cycle arrest. In addition, p21-overexpressing endothelial cells were highly sensitive for TNF-α induced-apoptosis. Surprisingly, senescence-associated β-galactosidase activity was not apparant in p21-infected endothelial cells, suggesting further signaling events necessary for the senescent morphology of endothelial cells.
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页码:117 / 124
页数:7
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