Nature Genetics35, 229 - 237 (2003)
Published online: 12 October 2003; | doi:10.1038/ng1254
Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel−Lindau protein
Paul G Corn1, E Robert McDonald III1, James G Herman2
& Wafik S El-Deiry1
1
Department of Medicine, Howard Hughes Medical Institute and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
The Johns Hopkins Oncology Center, Baltimore, Maryland 21287, USA.
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 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 -domain of pVHL and complexes with pVHL and Hif1in vivo. Overexpression of TBP-1 promotes degradation of Hif1 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. 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, but not TBP-1, and does not promote degradation of Hif1. Thus, the ability of pVHL to degrade Hif1 depends in part on its interaction with TBP-1 and suggests a new mechanism for Hif1 stabilization in some pVHL-deficient tumors.
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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 
-domain of pVHL and complexes with pVHL and Hif1
chains activated by prolyl hydroxylation
