TAp63gamma (p51A) and dNp63alpha (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression

Oncogene. 2002 Apr 11;21(16):2455-65. doi: 10.1038/sj.onc.1205330.

Abstract

Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identified as a p53-relative, encodes multiple isoforms with structural and functional similarities and differences from p53. In this study, we show the evidence that the two major isoforms of the p63 gene, TAp63gamma (p51A) and dNp63alpha (p73L), represses and upregulates VEGF expression, respectively, on transcription and protein levels. Transient transfection assays show that a hypoxia-inducible factor (HIF) 1 binding site within the VEGF promoter region is responsible for both upregulation and repression by dNp63alpha and by TAp63gamma, respectively, of the VEGF promoter activity. We also show that TAp63gamma targets HIF1alpha for promoting proteasomal degradation but that dNp63alpha targets HIF1alpha for stabilization. Mammalian two-hybrid assays show that HIF1alpha-dependent transcription is repressed by TAp63gamma as well as by p53, whereas it is upregulated by dNp63alpha in collaboration with a transcription coactivator p300. Our data also show that dNp63alpha acts as a dominant-negative reagent toward both p53- and TAp63gamma-mediated degradation of HIF1alpha and repression of HIF1alpha-dependent transcription. These results suggest that p63 is involved in the regulation of the VEGF gene expression and that modulation of VEGF expression by TAp63gamma and dNp63alpha is closely correlated with their distinct roles on the regulation of HIF1alpha stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Endothelial Growth Factors / biosynthesis
  • Endothelial Growth Factors / genetics*
  • Gene Silencing
  • Genes, Tumor Suppressor
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines / biosynthesis
  • Lymphokines / genetics*
  • Membrane Proteins*
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Promoter Regions, Genetic
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • RNA, Messenger / biosynthesis
  • Response Elements
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins
  • Up-Regulation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • CKAP4 protein, human
  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines
  • Membrane Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Protein Isoforms
  • RNA, Messenger
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Trp63 protein, mouse
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors