a dominant-negative ppar mutant promotes cell cycle progression and cell growth in vascular smooth muscle cells一个显性负ppar突变促进细胞周期进程和细胞生长在血管平滑肌细胞.pdfVIP

Hindawi Publishing Corporation PPAR Research Volume 2009, Article ID 438673, 10 pages doi:10.1155/2009/438673 Research Article A Dominant-Negative PPARγ Mutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells Joey Z. Liu,1 Christopher J. Lyon,1 Willa A. Hsueh,1 and Ronald E. Law2 1 The Methodist Hospital Research Institute, Houston, TX 77030, USA 2 Takeda America Holdings, Deerfield, IL 60015, USA Correspondence should be addressed to Willa A. Hsueh, wahsueh@ Received 3 September 2009; Accepted 24 November 2009 Recommended by Tianxin Yang PPARγ ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant- negative (DN) PPARγ mutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPARγ promoted G1 → S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARγ expression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPARγ inhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARγ expression, however, did not up-regulate positive cell cycle regulators in PPARγ-deficient cells, strongly suggesting that DN-PPARγ effects on cell cycle result from blocking the function of endogenous wild-type PPARγ. DN-PPARγ expression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARγ-induced phosphorylation of Rb and expr