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

52 Citations (Scopus)

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
StatePublished - Feb 1 2002

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Cyclin A
Endothelial cells
Cell growth
Homocysteine
Endothelial Cells
Growth
Cyclin E
Phosphotransferases
Cyclin D1
Cells
Messenger RNA
Cell Cycle
Transcription
S Phase
Vascular Smooth Muscle
Mitogens
Adenoviridae
Smooth Muscle Myocytes
Transfection
Half-Life

ASJC Scopus subject areas

  • Hematology

Cite this

Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition. / Wang, Hong; Jiang, Xiaohua; Yang, Fan; Chapman, Gary B.; Durante, William; Sibinga, Nicholas E.S.; Schafer, Andrew I.

In: Blood, Vol. 99, No. 3, 01.02.2002, p. 939-945.

Research output: Contribution to journalArticle

Wang, Hong ; Jiang, Xiaohua ; Yang, Fan ; Chapman, Gary B. ; Durante, William ; Sibinga, Nicholas E.S. ; Schafer, Andrew I. / Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition. In: Blood. 2002 ; Vol. 99, No. 3. pp. 939-945.
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