Activation of Sp1-mediated Vascular Permeability Factor/Vascular Endothelial Growth Factor Transcription Requires Specific Interaction with Protein Kinase C ζ
Vascular Endothelial Growth Factor A
0301 basic medicine
Lymphokines
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
DOI:
10.1074/jbc.273.41.26277
Publication Date:
2002-07-26T15:02:22Z
AUTHORS (4)
ABSTRACT
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.
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