Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines

Nature. 2001 Sep 20;413(6853):311-6. doi: 10.1038/35095068.


During Drosophila development and mammalian embryogenesis, exit from the cell cycle is contingent on tightly controlled downregulation of the activity of Cyclin E-Cdk2 complexes that normally promote the transition from G1 to S phase. Although protein degradation has a crucial role in downregulating levels of Cyclin E, many of the proteins that function in degradation of Cyclin E have not been identified. In a screen for Drosophila mutants that display increased cell proliferation, we identified archipelago, a gene encoding a protein with an F-box and seven tandem WD (tryptophan-aspartic acid) repeats. Here we show that archipelago mutant cells have persistently elevated levels of Cyclin E protein without increased levels of cyclin E RNA. They are under-represented in G1 fractions and continue to proliferate when their wild-type neighbours become quiescent. The Archipelago protein binds directly to Cyclin E and probably targets it for ubiquitin-mediated degradation. A highly conserved human homologue is present and is mutated in four cancer cell lines including three of ten derived from ovarian carcinomas. These findings implicate archipelago in developmentally regulated degradation of Cyclin E and potentially in the pathogenesis of human cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Cell Division
  • Cell Transformation, Neoplastic* / genetics
  • Cyclin E / metabolism*
  • Drosophila
  • F-Box Proteins*
  • F-Box-WD Repeat-Containing Protein 7
  • Female
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Neoplasms / etiology
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Photoreceptor Cells, Invertebrate / cytology
  • Photoreceptor Cells, Invertebrate / metabolism
  • Protein Binding
  • Tumor Cells, Cultured
  • Ubiquitin-Protein Ligases*


  • Cell Cycle Proteins
  • Cyclin E
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Ubiquitin-Protein Ligases

Associated data

  • GENBANK/AF411971
  • GENBANK/AF411972