RB-dependent S-phase response to DNA damage.
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.
Knudsen
K E
KE
Department of Cell Biology, University of Cincinnati, Cincinnati, Ohio 45267-0521, USA. Erik.Knudsen@UC.edu
Booth
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Naderi
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Sever-Chroneos
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Fribourg
A F
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Hunton
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Feramisco
J R
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Wang
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Knudsen
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D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D009152:Mutagenicity Tests; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000187:drug effects; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016685:Mitomycin; D005047:Etoposide; D004247:DNA; D002945:Cisplatin