Regulation of hypoxia-inducible mRNAs 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 hypoxia-inducible mRNAs under normoxic (21% O2) 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.
Lonergan
K M
KM
Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Iliopoulos
O
O
Ohh
M
M
Kamura
T
T
Conaway
R C
RC
Conaway
J W
JW
Kaelin
W G
WG
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D044842:Cullin Proteins; D000075065:Elongin; D016147:Genes, Tumor Suppressor; D006801:Humans; D008025:Ligases; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
C105153:CUL2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; C000616395:ELOC protein, human; D000075065:Elongin; D046911:Macromolecular Substances; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human