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Peroxisome Proliferator-Activated Receptor Inhibits Expression of Minichromosome Maintenance Proteins in Vascular Smooth Muscle Cells

Division of Endocrinology, Diabetes and Hypertension and The Gonda (Goldschmied) Diabetes Center (D.B., F.Y., J.L., A.J.V.H., R.E.L.), David Geffen School of Medicine, University of California, Los Angeles, California 90095; Department of Medicine/Cardiology (D.B., E.F.), German Heart Institute, Berlin, D-13353, Germany; Merck Research Laboratories (J.P.B.), Rahway, New Jersey 07065; Virology Division (T.K.), National Cancer Center Research Institute, Tokyo,104-0045, Japan; and Division of Molecular Medicine and The Gonda Diabetes and Genetic Research Center, and the Department of Diabetes, Endocrinology, and Metabolism (J.C., B.M.F.), The City of Hope National Medical Center, Beckman Research Institute, Duarte, California 91010

Address all correspondence and requests for reprints to: Ronald E. Law, Ph.D, University of California, Los Angeles School of Medicine, Division of Endocrinology, Diabetes and Hypertension, Warren Hall, Suite 24-130, 900 Veteran Avenue, Los Angeles, California 90095. E-mail: rlaw{at}mednet.ucla.edu.

Using a cDNA array consisting only of cell cycle genes, we found that a novel nonthiazolidinedione partial peroxisome proliferator-activated receptor (PPAR) agonist (nTZDpa) inhibited expression of minichromosome maintenance (MCM) proteins 6 and 7 in vascular smooth muscle cells. 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. Inhibition of MCM6 and MCM7 expression by nTZDpa and rosiglitazone 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 vascular smooth muscle cell proliferation.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ

Ligands:   GW 9662  |  Rosiglitazone

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