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;

D O I：

暂无

中图分类号：

学科分类号：

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.

引用

页码：117 / 124

页数：7