Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition

Author:

Wang Hong1,Jiang XiaoHua1,Yang Fan1,Chapman Gary B.1,Durante William1,Sibinga Nicholas E. S.1,Schafer Andrew I.1

Affiliation:

1. From the Departments of Medicine and Pharmacology, Baylor College of Medicine, Department of Bioengineering, Rice University, and VA Medical Center, Houston, TX; and Medicine/Cardiology, Albert Einstein College of Medicine, New York, NY.

Abstract

Abstract Previously, it was reported that homocysteine (Hcy) specifically inhibits the growth of endothelial cells (ECs), suppresses Ras/mitogen-activated protein (MAP) signaling, and arrests cell growth at the G1/S transition of the cell cycle. The present study investigated the molecular mechanisms underlying this cell-cycle effect. Results showed that clinically relevant concentrations (50 μM) of Hcy significantly inhibited the expression of cyclin A messenger RNA (mRNA) in ECs in a dose- and time-dependent manner. G1/S-associated molecules that might account for this block were not changed, because Hcy did not affect mRNA and protein expression of cyclin D1 and cyclin E. Cyclin D1- and E-associated kinase activities were unchanged. In contrast, cyclin A–associated kinase activity and CDK2 kinase activity were markedly suppressed. Nuclear run-on assay demonstrated that Hcy decreased the transcription rate of the cyclin A gene but had no effect on the half-life of cyclin A mRNA. In transient transfection experiments, Hcy significantly inhibited cyclin A promoter activity in endothelial cells, but not in vascular smooth muscle cells. Finally, adenovirus-transduced cyclin A expression restored EC growth inhibition and overcame the S phase block imposed by Hcy. Taken together, these findings indicate that cyclin A is a critical functional target of Hcy-mediated EC growth inhibition.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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