p53-repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation

Ran Brosh, Reut Shalgi, Atar Liran, Gilad Landan, Katya Korotayev, Giang Huong Nguyen, Espen Enerly, Hilde Johnsen, Yosef Buganim, Hilla Solomon, Ido Goldstein, Shalom Madar, Naomi Goldfinger, Anne Lise Børresen-Dale, Doron Ginsberg, Curtis C. Harris, Yitzhak Pilpel, Moshe Oren, Varda Rotter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

Abstract

Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs (miRNAs) in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcriptional regulators, E2F and p53, their targets and a family of 15 miRNAs. Indicative of their significance, expression of these miRNAs is downregulated in senescent cells and in breast cancers harboring wild-type p53. These miRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these miRNAs silence antiproliferative genes, which themselves are E2F1 targets. Thus, miRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative miRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Taken together, these findings position miRNAs as novel key players in the mammalian cellular proliferation network.

Original languageAmerican English
Article number229
JournalMolecular Systems Biology
Volume4
DOIs
StatePublished - 2008
Externally publishedYes

Keywords

  • Breast cancer
  • Microarray
  • Senescence
  • miR-106
  • mir-155

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