REGULATION OF HYPOXIA-INDUCIBLE MESSENGER-RNAS BY THE VON-HIPPEL-LINDAU TUMOR-SUPPRESSOR PROTEIN REQUIRES BINDING TO COMPLEXES CONTAINING ELONGINS B C AND CUL2/

The von Hippel-Lindau tumor suppressor protein(pVHL) binds to elongins B and C and posttranscriptionally regulates the accumulation of hypox ia-inducible mRNAs under normoxic (21% O-2) conditions. Here we report that pVHL binds, via elongin C, to the human homolog of the Caenorhab ditis elegans Cul2 protein. Coimmunoprecipitation and chromatographic copurification data suggest that pVHL-Cul2 complexes exist in native c ells. pVHL mutants that were unable to bind to complexes containing el ongin C and Cul2 were likewise unable to inhibit the accumulation of h ypoxia-inducible mRNAs. A model for the regulation of hypoxia-inducibl e mRNAs by pVHL is presented based on the apparent similarity of elong in C and Cul2 to Skp1 and Cdc53, respectively. These latter proteins f orm complexes that target specific proteins for ubiquitin-dependent pr oteolysis.