Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs
MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans....
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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Public Library of Science
2012
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| Online Access: | http://hdl.handle.net/1721.1/69088 https://orcid.org/0000-0002-7029-7415 |
| _version_ | 1811079282803343360 |
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| author | Le, Minh T. N. Shyh-Chang, Ng Khaw, Swea Ling Chin, Lingzi Teh, Cathleen Tay, Junliang O'Day, Elizabeth M. Korzh, Vladimir Yang, Henry Lal, Ashish Lieberman, Judy Lim, Bing Lodish, Harvey F |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Le, Minh T. N. Shyh-Chang, Ng Khaw, Swea Ling Chin, Lingzi Teh, Cathleen Tay, Junliang O'Day, Elizabeth M. Korzh, Vladimir Yang, Henry Lal, Ashish Lieberman, Judy Lim, Bing Lodish, Harvey F |
| author_sort | Le, Minh T. N. |
| collection | MIT |
| description | MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain- and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA–target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis. |
| first_indexed | 2024-09-23T11:12:44Z |
| format | Article |
| id | mit-1721.1/69088 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:12:44Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/690882022-10-01T02:02:34Z Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs Le, Minh T. N. Shyh-Chang, Ng Khaw, Swea Ling Chin, Lingzi Teh, Cathleen Tay, Junliang O'Day, Elizabeth M. Korzh, Vladimir Yang, Henry Lal, Ashish Lieberman, Judy Lim, Bing Lodish, Harvey F Massachusetts Institute of Technology. Department of Biology Lodish, Harvey F. Lodish, Harvey F. MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain- and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA–target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis. Singapore. Agency for Science, Technology and Research L'Oréal Singapore (L'Oréal Singapore for Women in Science National Fellow) Singapore-MIT Alliance (grant C-382-641-001-091) United States. National Institutes of Health (grant R01 DK068348) United States. National Institutes of Health 2012-02-10T19:38:54Z 2012-02-10T19:38:54Z 2011-09 2011-03 Article http://purl.org/eprint/type/JournalArticle 1553-7390 1553-7404 http://hdl.handle.net/1721.1/69088 Le, Minh T. N. et al. “Conserved Regulation of P53 Network Dosage by MicroRNA–125b Occurs Through Evolving miRNA–Target Gene Pairs.” Ed. Michael T. McManus. PLoS Genetics 7.9 (2011): e1002242. Web. 10 Feb. 2012. https://orcid.org/0000-0002-7029-7415 en_US http://dx.doi.org/10.1371/journal.pgen.1002242 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Le, Minh T. N. Shyh-Chang, Ng Khaw, Swea Ling Chin, Lingzi Teh, Cathleen Tay, Junliang O'Day, Elizabeth M. Korzh, Vladimir Yang, Henry Lal, Ashish Lieberman, Judy Lim, Bing Lodish, Harvey F Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs |
| title | Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs |
| title_full | Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs |
| title_fullStr | Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs |
| title_full_unstemmed | Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs |
| title_short | Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs |
| title_sort | conserved regulation of p53 network dosage by microrna 125b occurs through evolving mirna target gene pairs |
| url | http://hdl.handle.net/1721.1/69088 https://orcid.org/0000-0002-7029-7415 |
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