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 Hif1α 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 β-domain of pVHL and complexes with pVHL and Hif1α in vivo. Overexpression of TBP-1 promotes degradation of Hif1α 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 Hif1α. Several distinct mutations in exon 2 of VHL disrupt binding of pVHL to TBP-1. A pVHL mutant containing a P154L substitution coimmunoprecipitates with Hif1α but not TBP-1, and does not promote degradation of Hif1α. Thus, the ability of pVHL to degrade Hif1α depends in part on its interaction with TBP-1 and suggests a new mechanism for Hif1α stabilization in some pVHL-deficient tumors.
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