ETS1 lowers capillary endothelial cell density at confluence and induces the expression of VE-cadherin

HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

“…This was based on our previous observation that Ets-1 is able to activate this region (Lelie`vre et al, 2000) and on the fact that Ets-1 was shown to interact with HIF-2a and to activate synergistically the flk-1 gene promoter (Elvert et al, 2003). Ets-1 and HIF-2a used alone activated the À2486Luc reporter 4.870.1-and 8.870.2-fold, respectively (Figure 8), while transfection of Ets-1 and HIF-2a VE-cadherin responds to ETS factors, including Ets-1, through two essential EBS, named EBS2 and EBS4, which are located in this proximal part of the promoter (Gory-Faure´et al, 1999;Lelie`vre et al, 2000). Mutation of either EBS2 or EBS4 abolished the synergy between Ets-1 and HIF-2a (Figure 8), yielding almost precisely …”

“…The VE-cadherin gene also contains a minimal (basal) promoter sequence, located in À139/ þ 24, which is active independently of the cell type (Gory et al, 1998. This promoter region is mainly regulated by a set of two EBS and a GT-box, which are necessary for the basal activity of the gene (Gory et al, 1998), both EBS being activated by Ets-1 isoforms (Lelie`vre et al, 2000;Lionneton et al, 2003). Interestingly, this part of the promoter does not contain any conventional HRE but still responds to HIF-2a to a significant extent (Figure 6), suggesting that coactivation of HIF-2a with another transcription factor independently of its binding to DNA could promote transcription of the gene or that unknown, specific, HIF-2a-response elements are activated in this region.…”

“…This region contains an active GT box and two Ets-binding sites (EBS), named EBS2 and EBS4, which are essential for expression (Gory et al, 1998). We have shown previously that overexpression of the Ets-1 transcription factor induces VE-cadherin expression by direct binding to these two EBS (Lelie`vre et al, 2000). The region that is responsible for the specific expression in endothelial cells is located in the À2486/ þ 24 part of the gene.…”

Angiogenesis: The VE-Cadherin Switch

“…Ets1 is thus a good candidate for transcriptional activation in the angiogenesis process. Given that Lelievre et al 2000 VE-cadherin VE-cadherin is involved in vascular morphogenesis and endothelial survival, the fact that its expression is upregulated during vascular proliferation further suggests that VE-cadherin may be a key player in this process.…”

Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice

“…41 VE-cadherin promoter has been characterized by our group and we have shown that it specifically drives reporter gene expression in the endothelium of transgenic mice. [42][43][44][45] Here, the antitumor activity of the TK/GCV system was tested in a primary tumor model implanted in VEcadherin/TK transgenic mice in order to substantiate the principle of an angiotoxic gene therapy.…”