Many high-throughput loss-of-function analyses of the eukaryotic cell cycle have relied on the unicellular yeast species Saccharomyces cerevisiae and Schizosaccharomyces pombe. In multicellular organisms, however, additional control mechanisms regulate the cell cycle to specify the size of the organism and its constituent organs¹. To identify such genes, here we analysed the effect of the loss of function of 70% of Drosophila genes (including 90% of genes conserved in human) on cell-cycle progression of S2 cells using flow cytometry. To address redundancy, we also targeted genes involved in protein phosphorylation simultaneously with their homologues. We identify genes that control cell size, cytokinesis, cell death and/or apoptosis, and the G1 and G2/M phases of the cell cycle. Classification of the genes into pathways by unsupervised hierarchical clustering on the basis of these phenotypes shows that, in addition to classical regulatory mechanisms such as Myc/Max, Cyclin/Cdk and E2F, cell-cycle progression in S2 cells is controlled by vesicular and nuclear transport proteins, COP9 signalosome activity and four extracellular-signal-regulated pathways (Wnt, p38MAPK, FRAP/TOR and JAK/STAT). In addition, by simultaneously analysing several phenotypes, we identify a translational regulator, eIF-3p66, that specifically affects the Cyclin/Cdk pathway activity.

1. Molecular and Cancer Biology Program, and
2. High Throughput Center, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland
3. Department of Molecular Medicine, National Public Health Institute, and
4. Biomedicum Bioinformatics Unit, Biomedicum, FI-00251 Helsinki, Finland
5. *These authors contributed equally to this work

Correspondence to: Minna Taipale^1,3,5Jussi Taipale^1,2,3 Correspondence and requests for materials should be addressed to J.T. (Email: jussi.taipale@helsinki.fi) and M.T. (Email: minna.taipale@helsinki.fi).

Received 13 June 2005; Accepted 21 November 2005

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