Retinoic Acids Repress the Expression of ETS-1 in Endothelial Cells.

Abstract

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.

Cell density-dependent regulation of matrix metalloproteinase and TIMP expression in differently tumorigenic breast cancer cell lines

“…Menashi and co-workers reported on enhanced binding of MMP-2 on the surface of nonconfluent breast cancer cells [9], although the underlying mechanisms of this observation were not investigated. Moreover, Igarashi and coworkers [10] observed upregulation of ets-1 mRNA in sparse cultures of endothelial cells. The transcription factor ETS-1 is also known to induce MMP-1, -3, and -9 [43,44].…”

“…However, a clear-cut proof therefore still is missing. Binding of MMP-2 to the cell surface has been found to be reduced [9] in confluent breast cancer cells, and transcription factors involved in MMP regulation, such as Ets, appear to be expressed at higher levels in sparse cultures of endothelial cells [10]. However, the dynamics and the factors regulating MMP expression in vivo are not well understood, as is the role of AP-1 in the regulation of major MMPs in biologically different settings.…”

Regulation of Vascular Inflammation and Remodeling by ETS Factors

“…Ets-1 has been shown to regulate genes involved in endothelial function and angiogenesis. [25][26][27][28][29][30] Ets-1 enhances endothelial migration by enhancing the expression of matrix metalloproteinases (MMPs) and ␤ 3 integrin. 31 Ets-1 also regulates the expression of other genes involved in angiogenesis including the vascular endothelial growth factor receptors and angiopoietin-2.…”

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“…Some factors have been shown to repress Ets1 expression. Wildtype p53, but not mutant p53, was found to repress the Ets1 promoter [15] and, in endothelial cells, retinoic acid negatively modulates Ets1 expression [168]. Different regions of the Ets1 promoter drive Ets1 expression during murine embryonal development [169].…”