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

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