1: Blood. 2002 Feb 1;99(3):939-45. 

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

Wang H, Jiang X, Yang F, Chapman GB, Durante W, Sibinga NE, Schafer AI.

Department of Medicine, Baylor College of Medicine, 2002 Holcombe Ave 109-129,
Houston, TX 77030, USA. hongw@bcm.tmc.edu

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 G(1)/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
microM) of Hcy significantly inhibited the expression of cyclin A messenger RNA
(mRNA) in ECs in a dose- and time-dependent manner. G(1)/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.

PMID: 11806997 [PubMed - indexed for MEDLINE]