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

Ran Brosh1, Reut Shalgi, Atar Liran

  • 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Molecular Systems Biology
|November 27, 2008
PubMed

Insights

MicroRNAs (miRNAs) are newly identified regulators of cell proliferation. These miRNAs, repressed by p53 and E2F1, control cell growth by silencing antiproliferative genes, impacting cancer and senescence.

Area of Science:

  • Molecular biology
  • Cellular biology
  • Genetics

Background:

  • Cell proliferation is tightly regulated by complex biological systems.
  • MicroRNAs (miRNAs) are increasingly recognized for their role in gene expression control.
  • The specific role of miRNAs in mammalian cell proliferation remains incompletely understood.

Purpose of the Study:

  • To investigate the role of a specific family of 15 miRNAs in the mammalian cell proliferation network.
  • To elucidate the interplay between miRNAs, p53, and E2F transcriptional regulators in controlling cell growth.

Main Methods:

  • Analysis of miRNA expression in senescent cells and breast cancer tissues.
  • Investigation of miRNA regulation by p53 and E2F1.
  • Assessment of miRNA function in silencing target antiproliferative genes.
  • Functional studies involving miRNA overexpression to observe effects on cell proliferation and senescence.

Main Results:

  • Expression of the studied miRNAs is downregulated in senescent cells and p53 wild-type breast cancers.
  • p53 represses these miRNAs through an E2F1-mediated pathway.
  • These miRNAs target and silence antiproliferative genes, which are also E2F1 targets.
  • Overexpression of these miRNAs promotes cell proliferation and delays senescence, similar to p53 inactivation.

Conclusions:

  • A novel multi-gene feed-forward loop involving miRNAs and transcriptional regulators (p53, E2F) controls mammalian cell proliferation.
  • MicroRNAs are critical components of the cellular proliferation network.
  • Perturbations in this miRNA-mediated regulatory circuit have significant phenotypic consequences, impacting cancer and aging.

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