| Distinct mechanisms act in concert to mediate cell cycle arrest. | |
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MedLine Citation:
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PMID: 19139404 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In response to DNA damage, cells arrest at specific stages in the cell cycle. This arrest must fulfill at least 3 requirements: it must be activated promptly; it must be sustained as long as damage is present to prevent loss of genomic information; and after the arrest, cells must re-enter into the appropriate cell cycle phase to ensure proper ploidy. Multiple molecular mechanisms capable of arresting the cell cycle have been identified in mammalian cells; however, it is unknown whether each mechanism meets all 3 requirements or whether they act together to confer specific functions to the arrest. To address this question, we integrated mathematical models describing the cell cycle and the DNA damage signaling networks and tested the contributions of each mechanism to cell cycle arrest and re-entry. Predictions from this model were then tested with quantitative experiments to identify the combined action of arrest mechanisms in irradiated cells. We find that different arrest mechanisms serve indispensable roles in the proper cellular response to DNA damage over time: p53-independent cyclin inactivation confers immediate arrest, whereas p53-dependent cyclin downregulation allows this arrest to be sustained. Additionally, p21-mediated inhibition of cyclin-dependent kinase activity is indispensable for preventing improper cell cycle re-entry and endoreduplication. This work shows that in a complex signaling network, seemingly redundant mechanisms, acting in a concerted fashion, can achieve a specific cellular outcome. |
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Authors:
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Jared E Toettcher; Alexander Loewer; Gerard J Ostheimer; Michael B Yaffe; Bruce Tidor; Galit Lahav |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-01-12 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 106 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2009-01-21 Completed Date: 2009-02-05 Revised Date: 2011-04-11 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 785-90 Citation Subset: IM |
Affiliation:
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Department of Biological Engineering, Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Cycle* Cyclin-Dependent Kinase Inhibitor p21 / physiology Cyclins / analysis DNA Damage* G1 Phase G2 Phase HCT116 Cells Humans Models, Biological Tumor Suppressor Protein p53 / physiology |
| Grant Support | |
ID/Acronym/Agency:
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GM083303/GM/NIGMS NIH HHS; P50 GM58762/GM/NIGMS NIH HHS; R01 GM065418-07/GM/NIGMS NIH HHS; R01 GM083303-03/GM/NIGMS NIH HHS; U54 CA112967/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Tumor Suppressor Protein p53 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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