| 5-ASA affects cell cycle progression in colorectal cells by reversibly activating a replication checkpoint. | |
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MedLine Citation:
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PMID: 17241873 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: Individuals with inflammatory bowel disease are at risk of developing colorectal cancer (CRC). Epidemiologic, animal, and laboratory studies suggest that 5-amino-salicylic acid (5-ASA) protects from the development of CRC by altering cell cycle progression and by inducing apoptosis. Our previous results indicate that 5-ASA improves replication fidelity in colorectal cells, an effect that is active in reducing mutations. In this study, we hypothesized that 5-ASA restrains cell cycle progression by activating checkpoint pathways in colorectal cell lines, which would prevent tumor development and improve genomic stability. METHODS: CRC cells with different genetic backgrounds such as HT29, HCT116, HCT116(p53-/-), HCT116+chr3, and LoVo were treated with 5-ASA for 2-96 hours. Cell cycle progression, phosphorylation, and DNA binding of cell cycle checkpoint proteins were analyzed. RESULTS: We found that 5-ASA at concentrations between 10 and 40 mmol/L affects cell cycle progression by inducing cells to accumulate in the S phase. This effect was independent of the hMLH1, hMSH2, and p53 status because it was observed to a similar extent in all cell lines under investigation. Moreover, wash-out experiments demonstrated reversibility within 48 hours. Although p53 did not have a causative role, p53 Ser15 was strongly phosphorylated. Proteins involved in the ATM-and-Rad3-related kinase (ATR)-dependent S-phase checkpoint response (Chk1 and Rad17) were also phosphorylated but not ataxia telengectasia mutated kinase. CONCLUSIONS: Our data demonstrate that 5-ASA causes cells to reversibly accumulate in S phase and activate an ATR-dependent checkpoint. The activation of replication checkpoint may slow down DNA replication and improve DNA replication fidelity, which increases the maintenance of genomic stability and counteracts carcinogenesis. |
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Authors:
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M Gloria Luciani; Christoph Campregher; John M Fortune; Thomas A Kunkel; Christoph Gasche |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2006-10-12 |
Journal Detail:
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Title: Gastroenterology Volume: 132 ISSN: 0016-5085 ISO Abbreviation: Gastroenterology Publication Date: 2007 Jan |
Date Detail:
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Created Date: 2007-01-23 Completed Date: 2007-03-14 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: United States |
Other Details:
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Languages: eng Pagination: 221-35 Citation Subset: AIM; IM |
Affiliation:
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Medical University of Vienna, Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Währinger Gürtel 18, A-1090 Vienna, Austria. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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metabolism Anti-Inflammatory Agents, Non-Steroidal / pharmacology* Apoptosis / drug effects Carrier Proteins / genetics, metabolism Cell Cycle / drug effects Cell Cycle Proteins / metabolism Cell Division / drug effects Colorectal Neoplasms / pathology, prevention & control* DNA Mismatch Repair / drug effects DNA Polymerase III / metabolism DNA Replication / drug effects*, physiology DNA-Binding Proteins / metabolism Flow Cytometry HT29 Cells Humans Mesalamine / pharmacology* Mitosis / drug effects Nuclear Proteins / genetics, metabolism Protein Kinases / metabolism Protein-Serine-Threonine Kinases / metabolism S Phase / drug effects Tumor Suppressor Protein p53 / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P 18270-B14//Austrian Science Fund FWF |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/CDC45 protein, human; 0/CLSPN protein, human; 0/Carrier Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/MCM2 protein, human; 0/MCM7 protein, human; 0/MLH1 protein, human; 0/Nuclear Proteins; 0/Rad17 protein, human; 0/Tumor Suppressor Protein p53; 89-57-6/Mesalamine; EC 2.7.-/Protein Kinases; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.7.-/DNA Polymerase III |
| Comments/Corrections | |
Comment In:
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Gastroenterology. 2007 Apr;132(4):1635-6; author reply 1636
[PMID:
17418160
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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