| miR-192 Regulates dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit. | |
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MedLine Citation:
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PMID: 19088023 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: The purpose of this study is to investigate the molecular mechanism of miR-192 in colon cancer. EXPERIMENTAL DESIGN: Human colon cancer cell lines with different p53 status were used as our model system to study the effect of miR-192 on cell proliferation, cell cycle control, and mechanism of regulation. RESULTS: Our results show that one of the key miR-192 target genes is dihydrofolate reductase (DHFR). miR-192 affects cellular proliferation through the p53-miRNA circuit. Western immunoblot analyses indicated that the expression of DHFR was significantly decreased by miR-192. Further investigation revealed that such suppression was due to translational arrest rather than mRNA degradation. More profound inhibition of cellular proliferation was observed by ectopic expression of miR-192 in colon cancer cell lines containing wild-type p53 than cells containing mutant p53. Thus, the effect of miR-192 on cellular proliferation is mainly p53 dependent. Overexpression of miR-192 triggered both G1 and G2 arrest in HCT-116 (wt-p53) cells but not in HCT-116 (null-p53) cells. The cell cycle checkpoint control genes p53 and p21 were highly overexpressed in cells that overexpressed miR-192. Endogenous miR-192 expression was increased in HCT-116 (wt-p53) and RKO (wt-p53) cells treated with methotrexate, which caused an induction of p53 expression. Chromatin immunoprecipitation-quantitative reverse transcription-PCR analysis revealed that the p53 protein interacted with the miR-192 promoter sequence. CONCLUSION: These results indicate that miR-192 may be another miRNA candidate that is involved in the p53 tumor suppressor network with significant effect on cell cycle control and cell proliferation. |
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Authors:
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Bo Song; Yuan Wang; Kenji Kudo; Elaine J Gavin; Yaguang Xi; Jingfang Ju |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 14 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2008 Dec |
Date Detail:
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Created Date: 2008-12-17 Completed Date: 2009-01-06 Revised Date: 2013-04-17 |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 8080-6 Citation Subset: IM |
Affiliation:
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Translational Research Laboratory, Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794-8691, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Cycle Cell Proliferation Gene Expression Regulation, Enzymologic* HCT116 Cells HT29 Cells Humans Methotrexate / pharmacology MicroRNAs / physiology* Promoter Regions, Genetic Tetrahydrofolate Dehydrogenase / genetics* Tumor Suppressor Protein p53 / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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CA114043/CA/NCI NIH HHS; MH075020/MH/NIMH NIH HHS; R21 CA114043/CA/NCI NIH HHS; R21 CA114043-01A1/CA/NCI NIH HHS; R21 CA114043-02/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/MicroRNAs; 0/Tumor Suppressor Protein p53; 59-05-2/Methotrexate; EC 1.5.1.3/Tetrahydrofolate Dehydrogenase |
| Comments/Corrections | |
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