Conserved regulation of p53 network dosage by microRNA-125b occurs through evolving miRNA-target gene pairs

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

130 Scopus Citations
View graph of relations

Author(s)

  • Ng Shyh-Chang
  • Swea Ling Khaw
  • Lingzi Chin
  • Cathleen Teh
  • Junliang Tay
  • Elizabeth O'Day
  • Vladimir Korzh
  • Henry Yang
  • Ashish Lal
  • Judy Lieberman
  • Harvey F. Lodish
  • Bing Lim

Detail(s)

Original languageEnglish
Article numbere1002242
Journal / PublicationPLoS Genetics
Volume7
Issue number9
Publication statusPublished - Sep 2011
Externally publishedYes

Link(s)

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. © 2011 Le T. N. et al.

Research Area(s)

Citation Format(s)

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; Korzh, Vladimir; Yang, Henry; Lal, Ashish; Lieberman, Judy; Lodish, Harvey F.; Lim, Bing.

In: PLoS Genetics, Vol. 7, No. 9, e1002242, 09.2011.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review