Abstract
We investigated the functional effects of microRNA-34a (miR-34a) on c-Myc transcriptional complexes in renal cell carcinoma. miR-34a down-regulated expression of multiple oncogenes including c-Myc by targeting its 3' untranslated region, which was revealed by luciferase reporter assays. miR-34a was also found to repress RhoA expression by suppressing the c-Myc-Skp2-Miz1 transcriptional complex that activates RhoA. Overexpression of c-Myc reversed miR-34a suppression of RhoA expression and inhibition of cell invasion, suggesting that miR-34a inhibits invasion by suppressing RhoA through c-Myc. miR-34a was also found to repress the c-Myc-P-TEFb transcription elongation complex, indicating one of the mechanisms by which miR-34a has profound effects on cellular functions. Our results demonstrate that miR-34a suppresses assembly and function of the c-Myc complex that activates or elongates transcription, indicating a novel role of miR-34a in the regulation of transcription by c-Myc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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3' Untranslated Regions
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Carcinoma, Renal Cell / genetics*
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Down-Regulation
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Kidney Neoplasms / genetics*
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Neoplasm Invasiveness
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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S-Phase Kinase-Associated Proteins / genetics
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S-Phase Kinase-Associated Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptional Activation
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Tumor Cells, Cultured
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rhoA GTP-Binding Protein / genetics
Substances
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3' Untranslated Regions
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Kruppel-Like Transcription Factors
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MIRN34 microRNA, human
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MYC protein, human
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MicroRNAs
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Proto-Oncogene Proteins c-myc
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S-Phase Kinase-Associated Proteins
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Transcription Factors
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ZBTB17 protein, human
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RHOA protein, human
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rhoA GTP-Binding Protein