Abstract
Microtubule-disruption (MTD) is often thought to arrest the mammalian cell cycle only during mitosis. However, MTD has also been demonstrated to arrest cells during interphase at a G(1)-phase point we call G(1)MTA. Microtubule integrity is now shown to be required for progression past G(1)MTA and the mammalian restriction-point. Neither p21(waf1) nor p27(kip1) are required for MTD-induced G(1)-arrest. Only p21(waf1) is crucial for normal G(1)MTA passage. The p21(waf1)-Chk1-cdc25C-cdc2-checkpoint-pathway is implicated in monitoring this passage. P21(waf1) deletion deregulates G(1)MTA transition and decreases MTD-G(1) arrest, possibly via Chk1 disregulation. Oncogene-induced overexpression of p21(waf1) produced opposite effects on the Chk1-cdc25C-cdc2 pathway and enhanced MTD-G(1) arrest. G(1)MTA thus represents a novel facet of mammalian G(1)/S checkpoint.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Cycle Proteins / analysis
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Checkpoint Kinase 1
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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Cyclins / physiology*
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Etoposide / pharmacology
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G1 Phase / drug effects
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G1 Phase / physiology*
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Gene Deletion
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Humans
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Interphase
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Mice
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Mice, Knockout
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Microtubules / physiology*
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Nocodazole / pharmacology
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Phosphorylation
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Protein Kinases / metabolism
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Protein Kinases / physiology*
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Protein-Tyrosine Kinases / metabolism
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S Phase
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Signal Transduction
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cdc25 Phosphatases / analysis
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cdc25 Phosphatases / metabolism
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Etoposide
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Protein Kinases
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Protein-Tyrosine Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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CDC25C protein, human
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Cdc25c protein, mouse
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cdc25 Phosphatases
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Nocodazole