Expression of an Ets-1 dominant-negative mutant perturbs normal and tumor angiogenesis in a mouse ear model

Abstract

We and others have shown that members of the Ets family of transcription factors are involved in morphogenic properties of endothelial cells in vitro. To investigate the role of these factors in the transcriptional regulation of angiogenesis in vivo, we set up a nontraumatic model that allows daily macroscopic examination of both growth factor-and tumor-induced angiogenesis in mouse ears. In the same animal, we were thus able to record variations in the patterns of neovessels induced and cell populations recruited by the angiogenic factors FGF-2 and VEGF. In this model, inhibition of FGF-2-induced angiogenesis by the pharmacological compound TNP-470 was readily observed, demonstrating that the mouse ear model is also useful in the evaluation of antiangiogenic strategies. Our functional analysis of Ets transcription factors activity utilized a competitor protein, Ets1-DB, a dominant negative Ets1 mutant lacking the transactivation domain. Retrovirus-mediated expression of Ets1-DB inhibited FGF-2-induced angiogenesis, while the expression of Ets1-DB in cancerous and stromal cells disturbed tumorinduced angiogenesis. These results illustrate the value of the ear model and highlight the role of Ets family members in the transcriptional regulation of tumor angiogenesis.

The human VE-cadherin promoter is subjected to organ-specific regulation and is activated in tumour angiogenesis

“…This cytokine can induce expression of several transcription factors in endothelial cells, such as EGR1, Sp1 and HoxD3 (Boudreau et al, 1997;Khachigian and Collins, 1997;Kurz et al, 2003). Furthermore, Ets transcription factors were recently shown to be involved in bFGF-induced angiogenesis (Pourtier-Manzanedo et al, 2003). Further work is necessary to determine which pathway is activated in bFGF-dependent VE-cadherin induction.…”

Endothelial Function of von Hippel-Lindau Tumor Suppressor Gene: Control of Fibroblast Growth Factor Receptor Signaling

“…The ETS1 transcription factor is activated after ERK1/2 signaling in many cell types and is specifically expressed in endothelial cells undergoing tumor-induced and developmental angiogenesis (36,37). Also, the in vivo angiogenic effect of bFGF can be blocked by dominant-negative ETS1 construct (38). We therefore examined the role of ETS1 in VHL knockdown HMVECs.…”

Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1

“…To investigate the function of Ets-2, adenoviruses (Ad) encoding -galactosidase (LacZ, control), Ets-2, and TM-Ets-1, a dominant-negative Ets mutant ( Fig. 3A) (Nakano et al, 2000;Pourtier-Manzanedo et al, 2003), were also intraperitoneally administered twice a week. By 16 days, inflammatory plaques consisting mainly of macrophages had formed on the peritoneal surface of the diaphragm.…”