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Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

J Averous1, B D Fonseca, C G Proud

  • 1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.

Oncogene
|August 29, 2007
PubMed

Insights

The mammalian target of rapamycin complex 1 (mTORC1) pathway regulates cell function. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is key in controlling cyclin D1 expression, impacting cancer cell proliferation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mammalian target of rapamycin (mTOR) signaling, particularly the mTOR complex 1 (mTORC1) pathway, is crucial for regulating cellular functions.
  • mTORC1 inhibition via rapamycin can arrest cancer cell proliferation, indicating its therapeutic potential.

Purpose of the Study:

  • To investigate the role of mTORC1 signaling in regulating cyclin D1 expression.
  • To elucidate the specific mechanisms by which mTORC1 affects cyclin D1 levels and cell proliferation.

Main Methods:

  • Utilized MCF7 breast adenocarcinoma cells to study the effects of rapamycin and leucine starvation on cyclin D1 expression.
  • Employed siRNA-mediated knock-down of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) to assess its role in regulating cyclin D1.
  • Analyzed cytoplasmic mRNA levels and polysomal association of cyclin D1 mRNA.

Main Results:

  • Rapamycin treatment decreased cyclin D1 levels in MCF7 cells without altering its mRNA levels.
  • Leucine starvation, a more profound impairment of mTORC1 signaling, affected cyclin D1 levels differently than rapamycin in certain cell types.
  • Knock-down of 4E-BP1 abolished rapamycin's effect on cyclin D1 expression and increased cyclin D1 mRNA's polysomal association.

Conclusions:

  • 4E-BP1 is identified as a critical regulator of cyclin D1 expression, independent of cytoplasmic mRNA level changes.
  • The findings suggest that modulating amino acid input to mTORC1, rather than solely relying on rapamycin, might be a more effective strategy to inhibit proliferation in some cancer types.

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