Retinoic acids repress the expression of ETS-1 in endothelial cells.
The transcription factor ETS-1 expressed in endothelial cells (ECs) regulates angiogenesis by inducing MMP-1, MMP-3, MMP-9, u-PA and integrin beta3 in endothelial cells (ECs). Here, we examined whether antiangiogenic retinoic acids affect the expression of ETS-1 in ECs. The expression of ets-1 mRNA was up-regulated in sparse to subconfluent ECs and down-regulated in confluent ECs. When confluent ECs were stimulated with basic fibroblast growth factor (bFGF), ets-1 mRNA was induced. All-trans retinoic acid (ATRA) as well as 9-cis retinoic acid reduced the augmented expression of ets-1 mRNA in both subconfluent ECs and bFGF-treated confluent ECs. This inhibitory effect of ATRA was dose dependent and was evident at a concentration as low as 10(-7) M. ATRA did not alter the stability of ets-1 mRNA. Moreover, promoter analysis indicated that ATRA repressed the expression of ets-1 mRNA at transcriptional level. As a result, ATRA reduced the binding of ETS-1 protein to the ETS binding motif. These results indicate that the anti-angiogenic effect of retinoic acids is mediated at least in part by the transcriptional repression of ets-1 mRNA in ECs.
Igarashi
T
T
Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Abe
M
M
Oikawa
M
M
Nukiwa
T
T
Sato
Y
Y
D000077556:Alitretinoin; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051379:Mice; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; D004247:DNA