Tid-1 interacts with the von Hippel-Lindau protein and modulates angiogenesis by destabilization of HIF-1alpha

Cancer Res. 2005 Apr 1;65(7):2520-5. doi: 10.1158/0008-5472.CAN-03-2735.

Abstract

The von Hippel-Lindau protein (pVHL) is a major tumor suppressor protein and also associated with the inhibition of angiogenesis via HIF-1alpha ubiquitination and proteasomal degradation. To further elucidate the biological activity of pVHL in angiogenesis, pVHL-interacting proteins were screened using the yeast two-hybrid system. We found that a mouse homologue of the long form of Drosophila tumor suppressor l(2)tid, Tid-1(L), directly interacts with pVHL in vitro and in vivo. Furthermore, Tid-1(L) protein; enhanced the interaction between HIF-1alpha and pVHL, leading to the destabilization of HIF-1alpha protein; therefore, Tid-1(L) protein decreased vascular endothelial growth factor expression and inhibited angiogenesis in vivo and in vitro. These findings propose that Tid-1(L) may play a critical role in pVHL-mediated tumor suppression by modulating the pVHL-dependent HIF-1alpha stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chorioallantoic Membrane / blood supply
  • Down-Regulation
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • HSP40 Heat-Shock Proteins
  • HeLa Cells
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neovascularization, Physiologic / physiology
  • Plasmids / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein

Substances

  • DNAJA3 protein, human
  • HIF1A protein, human
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Vascular Endothelial Growth Factor A
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human