ZFIN ID: ZDB-PUB-110922-3
Conserved Regulation of p53 Network Dosage by MicroRNA-125b Occurs through Evolving miRNA-Target Gene Pairs
Le, M.T., Shyh-Chang, N., Khaw, S.L., Chin, L., Teh, C., Tay, J., O'Day, E., Korzh, V., Yang, H., Lal, A., Lieberman, J., Lodish, H.F., and Lim, B.
Date: 2011
Source: PLoS Genetics   7(9): e1002242 (Journal)
Registered Authors: Korzh, Vladimir, Teh, Cathleen
Keywords: Zebrafish, MicroRNAs, Apoptosis, Genetic networks, Vertebrates, Fibroblasts, Gene regulation, Regulator genes
MeSH Terms:
  • 3' Untranslated Regions
  • 3T3 Cells
  • Animals
  • Apoptosis/genetics*
  • Cell Line
  • Cell Proliferation
  • Gene Expression Regulation*
  • Gene Regulatory Networks/genetics*
  • HEK293 Cells
  • Humans
  • Mice
  • MicroRNAs/genetics
  • MicroRNAs/metabolism*
  • Microinjections
  • Tumor Suppressor Protein p53/genetics*
  • Zebrafish
PubMed: 21935352 Full text @ PLoS Genet.
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ABSTRACT

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.

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