Activation of Sp1-mediated vascular permeability factor/vascular endothelial growth factor transcription requires specific interaction with protein kinase C zeta.
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.
Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
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Claffey
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Cohen
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Mukhopadhyay
D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016228:Endothelial Growth Factors / Q000235:genetics*; D005354:Fibrosarcoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008025:Ligases; D008222:Lymphokines / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099221:Protein Kinase C zeta
D016228:Endothelial Growth Factors; D008025:Ligases; D008222:Lymphokines; D011493:Protein Kinase C; D011506:Proteins; D011993:Recombinant Fusion Proteins; D016329:Sp1 Transcription Factor; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099221:Protein Kinase C zeta; C497446:VHL protein, human