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Rapamycin causes activation of protein phosphatase-2A1 and nuclear translocation of PCNA in CD4+ T cells

Peter W Morrow1, H Y Lim Tung, Hugh C Hemmings

  • 1Protein and Nucleic Acid Chemistry Laboratory, Norchit Biomedical Research Institute, Liverpool (Syracuse), NY 13088, USA.

Biochemical and Biophysical Research Communications
|September 17, 2004
PubMed

Insights

Rapamycin activates protein phosphatase-2A1, which complexes with proliferation cell nuclear antigen (PCNA). This pathway influences DNA synthesis, repair, and cell cycle control in T cells.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Rapamycin is a significant immunosuppressant drug with a critical clinical role.
  • The precise mechanism of action for rapamycin remains incompletely understood.
  • Rapamycin induces cell cycle arrest in various cell types, including T cells.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying rapamycin's immunosuppressive effects.
  • To investigate the role of protein phosphatase-2A1 and proliferation cell nuclear antigen (PCNA) in rapamycin's action.

Main Methods:

  • Experiments were conducted using a CD4+ T cell line.
  • Activation of protein phosphatase-2A1 and its complex formation with PCNA were analyzed.
  • PCNA translocation was monitored, and the effect of okadaic acid (a protein phosphatase 2A inhibitor) was assessed.

Main Results:

  • Rapamycin treatment led to the activation of protein phosphatase-2A1.
  • Activated protein phosphatase-2A1 formed a complex with proliferation cell nuclear antigen (PCNA).
  • Rapamycin induced PCNA translocation from the cytoplasm to the nucleus, an effect reversed by okadaic acid.

Conclusions:

  • These findings reveal a novel signal transduction pathway initiated by rapamycin.
  • This pathway involves rapamycin-activated protein phosphatase 2A, linking it to PCNA.
  • The pathway regulates critical cellular processes including DNA synthesis, DNA repair, cell cycle progression, and cell death.

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