期刊
CIRCULATION RESEARCH
卷 103, 期 10, 页码 1155-1163出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.186205
关键词
PPAR alpha; telomerase; smooth muscle cells; transcriptional regulation; p16(INK4a)
资金
- NIH [RO1 HL084611]
- American Diabetes Association [1-06-RA-17]
- Fulbright Research Scholar
- American Heart Association [0725313B, 0725620B, 0815514D]
Peroxisome proliferator-activated receptor (PPAR)alpha, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPAR alpha activation suppresses G(1)-> S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16(INK4a) (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPAR alpha is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPAR alpha activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependenttrans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect that was dependent on p16. The inhibition of cell proliferation by PPAR alpha activation was lost in VSMCs following TERT overexpression or knockdown, pointing to a key role of telomerase as a target for the antiproliferative effects of PPAR alpha. Finally, we demonstrate that PPAR alpha agonists suppress telomerase activation during the proliferative response following vascular injury, indicating that these findings are applicable in vivo. In concert, these results demonstrate that the antiproliferative effects of PPAR alpha in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade. (Circ Res. 2008; 103: 1155-1163.)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据