1. Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA

Correspondence to: Iswar K. Hariharan Correspondence and requests for materials should be addressed to I.K.H. (e-mail: Email: hariharan@helix.mgh.harvard.edu). The sequences for human Ago have been deposited in GenBank under accession numbers AF411971 ( form) and AF411972 ( form).

Abstract

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^{1, 2}. 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.

1. Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA

Correspondence to: Iswar K. Hariharan Correspondence and requests for materials should be addressed to I.K.H. (e-mail: Email: hariharan@helix.mgh.harvard.edu). The sequences for human Ago have been deposited in GenBank under accession numbers AF411971 ( form) and AF411972 ( form).