ACTIVATION OF SP1-MEDIATED VASCULAR-PERMEABILITY FACTOR VASCULAR ENDOTHELIAL GROWTH-FACTOR TRANSCRIPTION REQUIRES SPECIFIC INTERACTION WITHPROTEIN-KINASE-C-ZETA/

The transcription factor Sp1 is ubiquitously expressed and plays a sig nificant role in the constitutive and induced expression of a variety of mammalian genes and may even contribute to tumorigenesis. Here, we describe a novel pathway whereby Sp1 promotes the transcription of vas cular permeability factor/vascular endothelial growth factor (VPF/NEGF ), a potent angiogenic factor, by interacting directly and specificall y with protein kinase C zeta (PKC zeta) isoform in renal cell carcinom a. PKC zeta binds and phosphorylates the zinc finger region of Sp1. Mo reover, in the presence of the wild type von Hippel-Lindau gene produc t, the interaction of Sp1 with PKC zeta is inhibited, and in this mann er steady state levels of Sp1 phosphorylation are decreased significan tly. Co-transfection of renal cell carcinoma cells and human fibrosarc oma cells with a plasmid overexpressing PKC zeta and VPF/VEGF promoter luciferase constructs results in activation of Sp1-mediated transcrip tion, whereas expression of a dominant-negative mutant of PKC zeta rep ressed this activation. Taken together, our results suggest a new path way of cell signaling through PKC zeta and provide an insight into PKC zeta and Sp1-dependent transcriptional regulation of VPF/VEGF express ion and thus tumor angiogenesis,