Activation of Sp1-mediated Vascular Permeability Factor/Vascular Endothelial Growth Factor Transcription Requires Specific Interaction with Protein Kinase C ζ

• DOI: 10.1074/jbc.273.41.26277
• Publication Date: 2002-07-26T15:02:22Z
• Authors: Soumitro Pal; Kevin P. Claffey; Herbert T. Cohen; Debabrata Mukhopa...
• Keywords: Vascular Endothelial Growth Factor A; 0301 basic medicine; Lymphokines; 0303 health sciences; Transcription, Genetic; Sp1 Transcription Factor; Vascular Endothelial Growth Factors; Fibrosarcoma; Recombinant Fusion Proteins; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Proteins; Endothelial Growth Factors; Kidney Neoplasms; Ligases; 03 medical and health sciences; Tumor Cells, Cultured; Humans; Phosphorylation; Promoter Regions, Genetic; Carcinoma, Renal Cell; Protein Kinase C; Protein Binding

The transcription factor Sp1 is ubiquitously expressed and plays a significant 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 vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent angiogenic factor, by interacting directly and specifically with protein kinase C zeta (PKC zeta) isoform in renal cell carcinoma. PKC zeta binds and phosphorylates the zinc finger region of Sp1. Moreover, in the presence of the wild type von Hippel-Lindau gene product, the interaction of Sp1 with PKC zeta is inhibited, and in this manner steady state levels of Sp1 phosphorylation are decreased significantly. Co-transfection of renal cell carcinoma cells and human fibrosarcoma cells with a plasmid overexpressing PKC zeta and VPF/VEGF promoter luciferase constructs results in activation of Sp1-mediated transcription, whereas expression of a dominant-negative mutant of PKC zeta repressed this activation. Taken together, our results suggest a new pathway of cell signaling through PKC zeta and provide an insight into PKC zeta and Sp1-dependent transcriptional regulation of VPF/VEGF expression and thus tumor angiogenesis.