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Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21(Waf1/Cip1)

V Borgdorff1, M E Lleonart, C L Bishop

  • 1Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK.

Oncogene
|January 27, 2010
PubMed

Insights

Oncogene-induced senescence (OIS) prevents cancer. Researchers identified specific microRNAs (miRNAs) that, when overexpressed, can block OIS by preventing the upregulation of the cell cycle inhibitor p21(Waf1/Cip1).

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Oncogene-induced senescence (OIS) is a crucial tumor suppressive mechanism that halts proliferation upon oncogene activation.
  • Ras(G12V) oncogene expression in primary cells triggers OIS, acting as a safeguard against malignant transformation.
  • Understanding the molecular regulators of OIS is vital for cancer prevention strategies.

Purpose of the Study:

  • To identify key mediators, including microRNAs (miRNAs), that regulate oncogene-induced senescence (OIS).
  • To investigate the role of the cell cycle inhibitor p21(Waf1/Cip1) in OIS.
  • To discover novel miRNAs that can prevent Ras(G12V)-induced senescence.

Main Methods:

  • Genome-wide small interfering RNA (siRNA) and microRNA (miRNA) screening in human mammary epithelial cells (HMECs).
  • Assessing the effect of gene/miRNA knockdown or overexpression on Ras(G12V)-induced growth arrest.
  • Quantitative analysis of p21(Waf1/Cip1) expression levels.

Main Results:

  • siRNA-mediated knockdown of p21(Waf1/Cip1) rescued cells from Ras(G12V)-induced senescence.
  • A screen identified 28 miRNAs that prevented Ras(G12V)-induced growth arrest, including all members of the miR-106b family.
  • Overexpression of identified miRNAs, including miR-106b family members and similar sequences (miR-130b, miR-302 family, miR-512-3p, miR-515-3p), prevented Ras(G12V)-induced senescence by inhibiting p21(Waf1/Cip1) upregulation.

Conclusions:

  • The cell cycle inhibitor p21(Waf1/Cip1) plays a critical role in mediating OIS in human mammary epithelial cells.
  • Specific miRNAs, particularly the miR-106b family and related sequences, can modulate p21(Waf1/Cip1) activity and inhibit OIS.
  • These findings expand the known repertoire of miRNAs involved in tumor suppressor regulation and OIS.

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