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Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes

Christopher J Nelsen1, David G Rickheim, Melissa M Tucker

  • 1Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota 55415, USA.

The Journal of Biological Chemistry
|November 26, 2002
PubMed

Insights

Target of rapamycin signaling regulates cell growth and proliferation. This study identifies cyclin D1 as a key mediator, linking protein synthesis, cell growth, and proliferation downstream of this pathway in hepatocytes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Hepatology

Background:

  • Target of rapamycin (TOR) signaling is crucial for cellular responses to growth factors, including protein synthesis, cell growth, and proliferation.
  • The precise downstream mediators and the molecular links between growth and proliferation within the TOR pathway remain incompletely understood.

Purpose of the Study:

  • To elucidate the downstream mediators of TOR signaling that link growth factor-induced protein synthesis, cell growth, and proliferation in hepatocytes.
  • To investigate the role of cyclin D1 as a potential key mediator in this process.

Main Methods:

  • Experiments were conducted using cultured rat hepatocytes and in vivo mouse models.
  • Rapamycin was used to inhibit TOR signaling.
  • Cell cycle progression and protein synthesis were assessed.
  • Transfection studies were performed with cyclin D1, E2F2, cyclin E, and activated Akt.
  • Liver regeneration was studied in mice undergoing partial hepatectomy.

Main Results:

  • Rapamycin treatment inhibited hepatocyte proliferation, cell cycle protein upregulation, and global protein synthesis.
  • Overexpression of cyclin D1, but not cyclin E or activated Akt, rescued the rapamycin-induced cell cycle arrest and restored protein synthesis.
  • In vivo, rapamycin inhibited liver regeneration and cyclin D1 expression.
  • Transfection with cyclin D1 in rapamycin-treated mice restored hepatocyte proliferation, cell size, and liver growth.

Conclusions:

  • Cyclin D1 acts as a critical downstream mediator of TOR signaling in mitogen-stimulated hepatocytes.
  • Cyclin D1 is essential for linking TOR-mediated increases in protein synthesis, cell growth, and proliferation.
  • Targeting cyclin D1 may offer therapeutic strategies for conditions involving impaired liver regeneration or uncontrolled cell growth.

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