The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity.
The von Hippel-Lindau tumor suppressor (pVHL) is a component of an E3 ubiquitin ligase and targets hypoxia-inducible factor-1alpha (HIF-1alpha) for ubiquitylation and degradation under normoxic conditions. pVHL also directly inhibits HIF-1alpha transactivation by recruiting histone deacetylases. Here, we report a novel pVHL-interacting protein that functions as a negative regulator of ... HIF-1alpha transactivation. This protein, generated from the ZnF197 locus by alternative splicing, contains a Kruppel-associated box (KRAB)-A domain and a SCAN domain, but lacks the 22 C2H2-type zinc fingers present in ZnF197. Therefore, we named this protein pVHL-associated KRAB-A domain-containing protein (VHLaK). We demonstrate that the KRAB-A domain in VHLaK mediates pVHL binding and functions as a transcriptional repression module. The SCAN domain mediates VHLaK homo-oligomerization, which enhances VHLaK repressive activity. pVHL can recruit VHLaK to repress HIF-1alpha transcriptional activity and HIF-1alpha-induced VEGF expression. Finally, we demonstrate that pVHL, VHLaK and KAP1/TIF-1beta can be recruited into a single complex, indicating that KAP1/TIF-1beta may participate in pVHL-mediated transcriptional repression of HIF-1alpha. Our findings provide a novel mechanism for the modulation of HIF-1alpha transactivation by pVHL.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, DNA-Binding Proteins, Endothelial Growth Factors, Gene Expression Regulation, Genes, Tumor Suppressor, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Intercellular Signaling Peptides and Proteins, Ligases, Lymphokines, Molecular Sequence Data, Protein Structure, Tertiary, RNA, Messenger, Recombinant Fusion Proteins, Repressor Proteins, Sequence Alignment, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Von Hippel-Lindau Tumor Suppressor Protein
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, DNA-Binding Proteins, Endothelial Growth Factors, Gene Expression Regulation, Genes, Tumor Suppressor, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Intercellular Signaling Peptides and Proteins, Ligases, Lymphokines, Molecular Sequence Data, Protein Structure, Tertiary, RNA, Messenger, Recombinant Fusion Proteins, Repressor Proteins, Sequence Alignment, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Von Hippel-Lindau Tumor Suppressor Protein
EMBO J.
Date: Apr. 15, 2003
PubMed ID: 12682018
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