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Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14819-24. Epub 2006 Sep 25.

Genome-wide functional analysis of human cell-cycle regulators.

Author information

  • 1The Skaggs Institute for Chemical Biology, and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Abstract

Human cells have evolved complex signaling networks to coordinate the cell cycle. A detailed understanding of the global regulation of this fundamental process requires comprehensive identification of the genes and pathways involved in the various stages of cell-cycle progression. To this end, we report a genome-wide analysis of the human cell cycle, cell size, and proliferation by targeting >95% of the protein-coding genes in the human genome using small interfering RNAs (siRNAs). Analysis of >2 million images, acquired by quantitative fluorescence microscopy, showed that depletion of 1,152 genes strongly affected cell-cycle progression. These genes clustered into eight distinct phenotypic categories based on phase of arrest, nuclear area, and nuclear morphology. Phase-specific networks were built by interrogating knowledge-based and physical interaction databases with identified genes. Genome-wide analysis of cell-cycle regulators revealed a number of kinase, phosphatase, and proteolytic proteins and also suggests that processes thought to regulate G(1)-S phase progression like receptor-mediated signaling, nutrient status, and translation also play important roles in the regulation of G(2)/M phase transition. Moreover, 15 genes that are integral to TNF/NF-kappaB signaling were found to regulate G(2)/M, a previously unanticipated role for this pathway. These analyses provide systems-level insight into both known and novel genes as well as pathways that regulate cell-cycle progression, a number of which may provide new therapeutic approaches for the treatment of cancer.

PMID:
17001007
[PubMed - indexed for MEDLINE]
PMCID:
PMC1595435
Free PMC Article

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