Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein.

von Hippel-Lindau (VHL) gene inactivation occurs in von Hippel-Lindau (VHL) disease. The protein pVHL functions in a multi-subunit E3 ubiquitin ligase that targets the hypoxia-inducible transcription factor Hif1 alpha for proteasomal degradation during normoxia. We establish that pVHL binds to Tat-binding protein-1 (TBP-1), a component of the 19S regulatory complex ...
of the proteasome. TBP-1 associates with the beta-domain of pVHL and complexes with pVHL and Hif1 alpha in vivo. Overexpression of TBP-1 promotes degradation of Hif1 alpha in a pVHL-dependent manner that requires the ATPase domain of TBP-1. Blockade of TBP-1 expression by small interfering RNA (siRNA) causes prolonged degradation kinetics of Hif1 alpha. Several distinct mutations in exon 2 of VHL disrupt binding of pVHL to TBP-1. A pVHL mutant containing a P154L substitution coimmunoprecipitates with Hif1 alpha, but not TBP-1, and does not promote degradation of Hif1 alpha. Thus, the ability of pVHL to degrade Hif1 alpha depends in part on its interaction with TBP-1 and suggests a new mechanism for Hif1 alpha stabilization in some pVHL-deficient tumors.
Mesh Terms:
Base Sequence, DNA-Binding Proteins, Humans, Hydrolysis, Hypoxia-Inducible Factor 1, alpha Subunit, Molecular Sequence Data, Peptide Hydrolases, Proteasome Endopeptidase Complex, Protein Binding, RNA, Small Interfering, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Nat. Genet.
Date: Nov. 01, 2003
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