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Cited by 158MicroRNA in disease regulationCancer-related Molecular PathwaysCancer-related molecular mechanisms research

Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs

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Le, Minh T. N., Shyh-Chang, Ng, Khaw, Swea Ling, Chin, Lingzi, Teh, Cathleen, Tay, Junliang, O'Day, Elizabeth, Korzh, Vladimir +5 more·2011·PLoS Genetics
DOI 10.1371/journal.pgen.1002242PMC PMC3174204
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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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References 52 · Cited by 158

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Authors
Le, M. T. N., 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., & Lim, B.
Affiliations
  • Genome Institute of Singapore (SG)
  • National University of Singapore (SG)
  • Institute of Molecular and Cell Biology (SG)
  • Boston Children's Hospital (US)
  • Singapore Immunology Network (SG)
  • Whitehead Institute for Biomedical Research (US)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
  • Lodish, Harvey F.
  • Lim, Bing
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2011-09-15
Volume
7
Issue
9
Pages
e1002242
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1002242
PMC
PMC3174204
OpenAlex
W1533076763
Cited by
158
References
52
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 13 · 2021: 10 · 2020: 8 · 2019: 11 · 2018: 10 · 2017: 13 · 2016: 12 · 2015: 17 · 2014: 21 · 2013: 15 · 2012: 18
FWCI
5.99
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • National University of Singapore (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • Figshare (submittedVersion, cc-by)
  • PLoS eBooks
Funders
  • National Institutes of Health (DK068348)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068348)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
miR-125b, microRNA target regulation, miRNA-target pairs, evolutionary conservation, apoptosis regulators, cell cycle regulators, stem cell homeostasis, carcinogenesis
MeSH terms
Animals, Cell Line, Gene Expression Regulation, Humans, Microinjections, Zebrafish, Tumor Suppressor Protein p53, 3T3 Cells, Apoptosis, 3' Untranslated Regions, MicroRNAs, Cell Proliferation, Mice, Gene Regulatory Networks, HEK293 Cells

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