Document Detail

miR-192 Regulates dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit.
MedLine Citation:
PMID:  19088023     Owner:  NLM     Status:  MEDLINE    
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.
Bo Song; Yuan Wang; Kenji Kudo; Elaine J Gavin; Yaguang Xi; Jingfang Ju
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
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:
Created Date:  2008-12-17     Completed Date:  2009-01-06     Revised Date:  2013-06-04    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8080-6     Citation Subset:  IM    
Translational Research Laboratory, Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794-8691, USA.
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MeSH Terms
Cell Cycle
Cell Proliferation
Gene Expression Regulation, Enzymologic*
HCT116 Cells
HT29 Cells
Methotrexate / pharmacology
MicroRNAs / physiology*
Promoter Regions, Genetic
Tetrahydrofolate Dehydrogenase / genetics*
Tumor Suppressor Protein p53 / physiology*
Grant Support
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
Reg. No./Substance:
0/MicroRNAs; 0/Tumor Suppressor Protein p53; 59-05-2/Methotrexate; EC Dehydrogenase

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