期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 40, 页码 14819-14824出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0604320103
关键词
high-content screening; network analysis; small interfering RNA; human genome
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 Gi-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-kappa B 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.
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