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

Nature volume 413, pages 311–316 (2001)Cite this article

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 phase1,2. 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.

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Figure 1: ago mutant cells have a proliferative advantage over wild-type cells.
Figure 2: ago encodes a protein with an F-box and WD repeats, and its human orthologue is mutated in cancer cell lines.
Figure 3: ago inhibits accumulation of Cyclin E by a post-transcriptional mechanism.
Figure 4: Loss of ago alters regulation of the cell cycle.
Figure 5: Genetic and physical interaction between Archipelago and Cyclin E.

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Acknowledgements

We are indebted to C. Paulding for help with exon predictions, to S. Schelble for technical assistance, and to C. Pfleger, N. Dyson and O. Iliopoulos for comments on the manuscript. I.K.H. was funded by grants from the National Institutes of Health and the American Cancer Society (ACS) and K.H.M. was funded by a postdoctoral fellowship from the ACS.

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

    Kenneth H. Moberg, Daphne W. Bell, Doke C. R. Wahrer, Daniel A. Haber & Iswar K. Hariharan

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  1. Kenneth H. Moberg
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  2. Daphne W. Bell
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  5. Iswar K. Hariharan
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Corresponding author

Correspondence to Iswar K. Hariharan.

Supplementary information

Figure 1

(JPG 3.8 KB)

Cyclin B levels are not elevated in ago mutant clones. a-c, cyclin B levels (red) are not elevated in ago mutant clones that are marked by the absence of anti-bgal staining (blue). Arrowheads denote the morphogenetic furrow (MF). Arrows in a and c indicate ago mutant cells which continue to express Cyclin B within the MF. Scale bar = 10mm.

Table 1. Ago mutations in human cancer cell lines
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Moberg, K., Bell, D., Wahrer, D. et al. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413, 311–316 (2001). https://doi.org/10.1038/35095068

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