Castellano, L., Giamas, G., Jacob, J., Coombes, R. C., Lucchesi, W., Thiruchelvam, P., Barton, G., Jiao, L. R., Wait, R., Waxman, J., Hannon, G. J., Stebbing, J. (2009) The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response. Proceedings of the National Academy of Sciences of the United States of America, 106 (37). pp. 15732-15737. ISSN 00278424 (ISSN)
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Abstract
Following estrogenic activation, the estrogen receptor-α (ERα) directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) modulated by ERα have the potential to fine tune these regulatory systems and also provide an alternate mechanism that could impact on estrogen-dependent developmental and pathological systems. Through a microarray approach, we identify the subset of microRNAs (miRNAs) modulated by ERα, which include upregulation of miRNAs derived from the processing of the paralogous primary transcripts (pri-) mir-17-92 and mir-106a-363. Characterization of the mir-17-92 locus confirms that the ERα target protein c-MYC binds its promoter in an estrogen-dependent manner. We observe that levels of pri-mir-17-92 increase earlier than the mature miRNAs derived from it, implicating precursor cleavage modulation after transcription. Pri-mir-17-92 is immediately cleaved by DROSHA to pre-miR-18a, indicating that its regulation occurs during the formation of the mature molecule from the precursor. The clinical implications of this novel regulatory system were confirmed by demonstrating that pre-miR-18a was significantly upregulated in ERα-positive compared to ERα-negative breast cancers. Mechanistically, miRNAs derived from these paralogous pri-miRNAs (miR-18a, miR-19b, and miR-20b) target and downregulate ERα, while a subset of pri-miRNA-derived miRNAs inhibit protein translation of the ERα transcriptional p160 coactivator, AIB1. Therefore, different subsets of miRNAs identified act as part of a negative autoregulatory feedback loop. We propose that ERα, c-MYC, and miRNA transcriptional programs invoke a sophisticated network of interactions able to provide the wide range of coordinated cellular responses to estrogen.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | AIB1 Autoregulatory feedback loop Primary transcript Processing estrogen receptor alpha messenger RNA precursor microRNA Myc protein steroid receptor coactivator 3 article breast cancer controlled study down regulation gene locus human human cell microarray analysis molecular interaction molecular mechanics negative feedback oncogene c myc priority journal promoter region protein processing protein targeting RNA analysis RNA transcription transcription regulation upregulation 3' Untranslated Regions Breast Neoplasms Cell Line, Tumor Estradiol Female Humans MicroRNAs Ribonuclease III RNA Processing, Post-Transcriptional RNA, Neoplasm Transcription, Genetic Up-Regulation |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA |
| CSHL Authors: | |
| Communities: | CSHL labs > Hannon lab CSHL Cancer Center Shared Resources > Bioinformatics Service |
| Depositing User: | Matt Covey |
| Date: | 2009 |
| Date Deposited: | 09 Jan 2013 16:42 |
| Last Modified: | 05 Jan 2018 20:22 |
| PMCID: | PMC2747188 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/26442 |
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