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Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line

Author

Listed:
  • Heimo Strohmaier

    (MB-7, The Scripps Research Institute)

  • Charles H. Spruck

    (MB-7, The Scripps Research Institute)

  • Peter Kaiser

    (MB-7, The Scripps Research Institute)

  • Kwang-Ai Won

    (MB-7, The Scripps Research Institute)

  • Olle Sangfelt

    (CCK R8:03, Karolinska Hospital)

  • Steven I. Reed

    (MB-7, The Scripps Research Institute)

Abstract

Cyclin E, one of the activators of the cyclin-dependent kinase Cdk2, is expressed near the G1–S phase transition and is thought to be critical for the initiation of DNA replication and other S-phase functions1,2,3. Accumulation of cyclin E at the G1–S boundary is achieved by periodic transcription coupled with regulated proteolysis linked to autophosphorylation of cyclin E4. The proper timing and amplitude of cyclin E expression seem to be important, because elevated levels of cyclin E have been associated with a variety of malignancies5,6 and constitutive expression of cyclin E leads to genomic instability7. Here we show that turnover of phosphorylated cyclin E depends on an SCF-type protein-ubiquitin ligase that contains the human homologue of yeast Cdc4, which is an F-box protein containing repeated sequences of WD40 (a unit containing about 40 residues with tryptophan (W) and aspartic acid (D) at defined positions). The gene encoding hCdc4 was found to be mutated in a cell line derived from breast cancer that expressed extremely high levels of cyclin E.

Suggested Citation

  • Heimo Strohmaier & Charles H. Spruck & Peter Kaiser & Kwang-Ai Won & Olle Sangfelt & Steven I. Reed, 2001. "Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line," Nature, Nature, vol. 413(6853), pages 316-322, September.
    • Handle: RePEc:nat:nature:v:413:y:2001:i:6853:d:10.1038_35095076
    DOI: 10.1038/35095076
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