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
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Research Support, Non-U.S. Gov't
MeSH terms
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Chorioallantoic Membrane / blood supply
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Down-Regulation
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Endothelial Cells / cytology
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Endothelial Cells / metabolism
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HSP40 Heat-Shock Proteins
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HeLa Cells
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Neovascularization, Physiologic / physiology
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Plasmids / genetics
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Transcription Factors / metabolism*
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Transfection
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / genetics
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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DNAJA3 protein, human
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HIF1A protein, human
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HSP40 Heat-Shock Proteins
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Heat-Shock Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Messenger
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Transcription Factors
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Tumor Suppressor Proteins
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Ubiquitin
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Vascular Endothelial Growth Factor A
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human