Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs
Author(s)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.; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology
Public Library of Science
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.
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