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The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins.

The inactivation of the von Hippel-Lindau (VHL) gene predisposes affected individuals to VHL syndrome and is an early genetic event associated with sporadic renal cell carcinoma and CNS hemangioblastomas. The VHL protein (pVHL) has been shown to form a stable complex with elongin B and elongin C, two factors that stabilize and activate the transcription elongation factor elongin A. Here, Hs-CUL-2, a member of the recently identified multigene family, the cullins, is shown to specifically associate with the trimeric pVHL-elongin B-C (VBC) complex in vitro and in vivo. Nearly 70% of naturally occurring cancer-predisposing mutations of VHL disrupt this interaction. The pVHL-Hs-CUL-2 association is strictly dependent on the integrity of the trimeric VBC complex. Immunofluorescence studies show Hs-CUL-2 to be a cytosolic protein that can be translocated to the nucleus by pVHL. Recently it has been shown that a yeast Hs-CUL-2 homolog, Cdc53, is part of a ubiquitin protein ligase complex that targets cell cycle proteins for degradation by the ubiquitin proteolytic pathway. In Caenorhabditis elegans, a null mutation of another Hs-cul-2 homolog, Ce-cul-1, results in hyperplasia in all tissues and is required for cell cycle exit. Hence, Hs-cul-2 may be required for VHL function and, therefore, may be a candidate human tumor-suppressor gene.

Pubmed ID: 9122164


  • Pause A
  • Lee S
  • Worrell RA
  • Chen DY
  • Burgess WH
  • Linehan WM
  • Klausner RD


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 18, 1997

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Caenorhabditis elegans
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Cloning, Molecular
  • Cullin Proteins
  • Cytosol
  • Electrophoresis, Polyacrylamide Gel
  • Genes, Tumor Suppressor
  • HeLa Cells
  • Humans
  • Ligases
  • Molecular Sequence Data
  • Multigene Family
  • Peptide Fragments
  • Protein Biosynthesis
  • Proteins
  • Rats
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • von Hippel-Lindau Disease