Genome-wide functional analysis of human cell-cycle regulators.
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.
Mukherji
Mridul
M
The Skaggs Institute for Chemical Biology, and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bell
Russell
R
Supekova
Lubica
L
Wang
Yan
Y
Orth
Anthony P
AP
Batalov
Serge
S
Miraglia
Loren
L
Huesken
Dieter
D
Lange
Joerg
J
Martin
Christopher
C
Sahasrabudhe
Sudhir
S
Reinhardt
Mischa
M
Natt
Francois
F
Hall
Jonathan
J
Mickanin
Craig
C
Labow
Mark
M
Chanda
Sumit K
SK
Cho
Charles Y
CY
Schultz
Peter G
PG
D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D048749:Cytokinesis / Q000235:genetics; D015870:Gene Expression; D018816:Genes, cdc; D015894:Genome, Human / Q000235:genetics*; D015698:Genomic Library; D006801:Humans; D008938:Mitosis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D010641:Phenotype; D025941:Protein Interaction Mapping; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering