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

Hong Wang, Xiaohua Jiang, Fan Yang, Gary B. Chapman, William Durante, Nicholas E.S. Sibinga, Andrew I. Schafer

Research output: Contribution to journalArticle

54 Scopus citations

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 Hcymediated EC growth inhibition.

Original languageEnglish (US)
Pages (from-to)939-945
Number of pages7
JournalBlood
Volume99
Issue number3
DOIs
Publication statusPublished - Feb 1 2002

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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