Transforming growth factor-alpha -induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation

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Abstract
The endothelial cell‐specific mitogen vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) represents a central regulator of cutaneous angiogenesis. Increased VPF/VEGF expression has recently been reported in psoriatic skin and healing wounds, both conditions in which transforming growth factor‐α (TGFα) and its ligand, the epidermal growth factor receptor, are markedly up‐regulated. Since TGFα strongly induces VPF/VEGF synthesis in keratinocytes, TGFα‐mediated VPF/VEGF expression is likely to play a significant role in the initiation and maintenance of increased vascular hyperpermeability and hyperproliferation in skin biology. The objectives of the present studies were to determine the molecular mechanisms responsible for TGFα‐induced transcriptional activation of the VPF/VEGF gene. We have identified a GC‐rich TGFα‐responsive region between −88 bp and −65 bp of the VPF/VEGF promoter that is necessary for constitutive and TGFα‐inducible transcriptional activation. In electrophoretic mobility shift assays, this region binds Sp1‐dependent protein complexes constitutively and an additional TGFα‐inducible protein complex that is distinct from Sp1 protein. Both AP‐2 and Egr‐1 transcription factors were detected as components of the TGFα‐inducible protein complex in supershift EMSA studies. In co‐transfection studies, an AP‐2 but not an Egr‐1 expression vector activated VPF/VEGF transcription, thus indicating that AP‐2 protein is functionally important in TGFα‐induced VPF/VEGF gene expression. By clarifying regulatory mechanisms that are critical for angiogenic processes in the skin, these studies may form the basis for new therapeutic strategies to modulate VPF/VEGF expression in cutaneous inflammation and wound healing.