Regulation of Hypoxia-Inducible mRNAs by the von Hippel-Lindau Tumor Suppressor Protein Requires Binding to Complexes Containing Elongins B/C and Cul2
Abstract
Regulation of Hypoxia-Inducible mRNAs by the von Hippel-Lindau Tumor Suppressor Protein Requires Binding to Complexes Containing Elongins B/C and Cul2 Kim M. Lonergan 1 , 2 , Othon Iliopoulos 1 , 2 , Michael Ohh 1 , 2 , Takumi Kamura 3 , Ronald C. Conaway 3 , Joan Weliky Conaway 3 , 4 , 5 and William G. Kaelin Jr. 1 , 2 , * Dana-Farber Cancer Institute 1 and Brigham and Women’s Hospital, Harvard Medical School, 2 Boston, Massachusetts 02115; Program in Molecular and Cell Biology 3 and Howard Hughes Medical Institute, 4 Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104; and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190 5 Abstract The von Hippel-Lindau tumor suppressor protein (pVHL) binds to elongins B and C and posttranscriptionally regulates the accumulation of hypoxia-inducible mRNAs under normoxic (21% O 2 ) conditions. Here we report that pVHL binds, via elongin C, to the human homolog of the Caenorhabditis elegans Cul2 protein. Coimmunoprecipitation and chromatographic copurification data suggest that pVHL-Cul2 complexes exist in native cells. pVHL mutants that were unable to bind to complexes containing elongin C and Cul2 were likewise unable to inhibit the accumulation of hypoxia-inducible mRNAs. A model for the regulation of hypoxia-inducible mRNAs by pVHL is presented based on the apparent similarity of elongin C and Cul2 to Skp1 and Cdc53, respectively. These latter proteins form complexes that target specific proteins for ubiquitin-dependent proteolysis.