Abstract
The retinoblastoma tumor suppressor protein (RB) is a potent inhibitor of cell proliferation. RB is expressed throughout the cell cycle, but its antiproliferative activity is neutralized by phosphorylation during the G(1)/S transition. RB plays an essential role in the G(1) arrest induced by a variety of growth inhibitory signals. In this report, RB is shown to also be required for an intra-S-phase response to DNA damage. Treatment with cisplatin, etoposide, or mitomycin C inhibited S-phase progression in Rb(+/+) but not in Rb(-/-) mouse embryo fibroblasts. Dephosphorylation of RB in S-phase cells temporally preceded the inhibition of DNA synthesis. This S-phase dephosphorylation of RB and subsequent inhibition of DNA replication was observed in p21(Cip1)-deficient cells. The induction of the RB-dependent intra-S-phase arrest persisted for days and correlated with a protection against DNA damage-induced cell death. These results demonstrate that RB plays a protective role in response to genotoxic stress by inhibiting cell cycle progression in G(1) and in S phase.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Carrier Proteins*
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Cell Cycle Proteins*
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Cell Death / drug effects
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Cisplatin / pharmacology
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Cyclin A / antagonists & inhibitors
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Cyclin A / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / deficiency
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Cyclins / genetics
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Cyclins / physiology
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DNA / biosynthesis
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DNA Damage* / drug effects
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DNA Replication / drug effects
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DNA-Binding Proteins*
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E2F Transcription Factors
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Etoposide / pharmacology
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Fibroblasts
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Flow Cytometry
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Fluorescent Antibody Technique
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Gene Deletion
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Mice
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Mice, Knockout
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Mitomycin / pharmacology
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Mutagenicity Tests
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Phosphorylation / drug effects
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Rats
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism*
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Retinoblastoma-Binding Protein 1
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S Phase* / drug effects
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Transcription Factor DP1
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism
Substances
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Arid4a protein, mouse
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Carrier Proteins
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Cdkn1a protein, mouse
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Cdkn1a protein, rat
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Cell Cycle Proteins
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Cyclin A
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Mitomycin
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Etoposide
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DNA
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Cisplatin