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Submitted on December 9, 2002
Accepted on March 26, 2003
Inhibits Expression of Minichromosome Maintenance Proteins in Vascular Smooth Muscle Cells
1 Division of Endocrinology, Diabetes and Hypertension and The Gonda (Goldschmied) Diabetes Center, David Geffen School of Medicine, University of California, Los Angeles, CA-90095, USA, Department of Medicine/Cardiology, German Heart Institute, Berlin, D-13353, Germany, Merck Research Laboratories, Rahway, NJ-07065, USA, Virology Division, National Cancer Center Research Institute, Tokyo,104-0045, Japan, Division of Molecular Medicine and The Gonda Diabetes and Genetic Research Center, and the Department of Diabetes, Endocrinology, and Metabolism, The City of Hope National Medical Center, Beckman Coulter, Inc. Research Institute, Duarte, CA-91010, USA
* To whom correspondence should be addressed. E-mail: rlaw{at}mednet.ucla.edu,.
Using a cDNA array consisting only of cell cycle genes, we found that a novel non-thiazolidinedione partial peroxisome proliferator-activated receptor 
(PPAR) agonist (nTZDpa) inhibited expression of minichromosome maintenance (MCM) proteins 6 and 7 in vascular smooth muscle cells (VSMC). MCM proteins are required for the initiation and elongation stages of DNA replication and are regulated by the transcription factor E2F. Mitogen-induced MCM6 and MCM7 mRNA expression was potently inhibited by nTZDpa and to a lesser degree by the full PPAR agonist, rosiglitazone (RSG). Inhibition of MCM6 and MCM7 expression by nTZDpa and RSG paralleled their effect to inhibit phosphorylation of the retinoblastoma protein and cell proliferation. Transient transfection experiments revealed that the nTZDpa inhibited mitogen-induced MCM6 and MCM7 promoter activity implicating a transcriptional mechanism. Adenoviral-mediated E2F overexpression reversed the suppressive effect of nTZDpa on MCM6 and MCM7 expression. Furthermore, activity of a luciferase reporter plasmid driven by multiple E2F elements was inhibited by nTZDpa indicating that their down-regulation by nTZDpa involves an E2F-dependent mechanism. Overexpression of dominant-negative PPAR or addition of a PPAR antagonist, GW 9662, blocked nTZDpa inhibition of MCM7 transcription. Adenovirus-mediated overexpression of constitutively-active PPAR inhibited MCM7 expression in a similar manner as the nTZDpa. These findings provide strong evidence that activation of PPAR attenuates MCM7 transcription and support the important role of this nuclear receptor in regulating VSMC proliferation.
•
thiazolidinedione •
vascular smooth muscle •
proliferation •
E2F •
minichromosome maintenance protein
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