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dc.contributor.authorLe, Minh T. N.
dc.contributor.authorShyh-Chang, Ng
dc.contributor.authorKhaw, Swea Ling
dc.contributor.authorChin, Lingzi
dc.contributor.authorTeh, Cathleen
dc.contributor.authorTay, Junliang
dc.contributor.authorO'Day, Elizabeth M.
dc.contributor.authorKorzh, Vladimir
dc.contributor.authorYang, Henry
dc.contributor.authorLal, Ashish
dc.contributor.authorLieberman, Judy
dc.contributor.authorLim, Bing
dc.contributor.authorLodish, Harvey F
dc.date.accessioned2012-02-10T19:38:54Z
dc.date.available2012-02-10T19:38:54Z
dc.date.issued2011-09
dc.date.submitted2011-03
dc.identifier.issn1553-7390
dc.identifier.issn1553-7404
dc.identifier.urihttp://hdl.handle.net/1721.1/69088
dc.description.abstractMicroRNAs 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.en_US
dc.description.sponsorshipSingapore. Agency for Science, Technology and Researchen_US
dc.description.sponsorshipL'Oréal Singapore (L'Oréal Singapore for Women in Science National Fellow)en_US
dc.description.sponsorshipSingapore-MIT Alliance (grant C-382-641-001-091)en_US
dc.description.sponsorshipUnited States. National Institutes of Health (grant R01 DK068348)en_US
dc.description.sponsorshipUnited States. National Institutes of Healthen_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pgen.1002242en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/en_US
dc.sourcePLoSen_US
dc.titleConserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairsen_US
dc.typeArticleen_US
dc.identifier.citationLe, 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.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.approverLodish, Harvey F.
dc.contributor.mitauthorLodish, Harvey F.
dc.relation.journalPLoS Geneticsen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsLe, Minh T. N.; Shyh-Chang, Ng; Khaw, Swea Ling; Chin, Lingzi; Teh, Cathleen; Tay, Junliang; O'Day, Elizabeth; Korzh, Vladimir; Yang, Henry; Lal, Ashish; Lieberman, Judy; Lodish, Harvey F.; Lim, Bingen
dc.identifier.orcidhttps://orcid.org/0000-0002-7029-7415
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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