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Activation of c-Jun amino-terminal kinase by GDNF induces G2/M cell cycle delay linked with actin reorganization

Toshifumi Fukuda1, Naoya Asai, Atsushi Enomoto

  • 1Department of Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|June 22, 2005
PubMed

Insights

Glial cell line-derived neurotrophic factor (GDNF) causes a G2/M cell cycle delay in neuroectodermal tumor cells. This delay involves the Rac1/c-Jun NH2-terminal kinase (JNK) pathway, impacting cell division and actin organization.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The cell cycle is regulated by cyclin/cyclin-dependent kinase (Cdk) complexes, with their activity modulated by various signaling molecules.
  • Dysregulation of cell cycle control is a hallmark of cancer, making it a critical target for therapeutic intervention.

Purpose of the Study:

  • To investigate the effect of glial cell line-derived neurotrophic factor (GDNF) on the cell cycle progression of human SK-N-MC neuroectodermal tumor cells.
  • To elucidate the molecular mechanisms underlying GDNF-induced cell cycle modulation, focusing on key regulatory proteins and signaling pathways.

Main Methods:

  • Treatment of SK-N-MC cells with GDNF.
  • Analysis of cell cycle phase distribution using flow cytometry.
  • Assessment of protein expression and phosphorylation states of Cdc2, cyclin B1, and Wee1 kinase via Western blotting and immunohistochemistry.
  • Investigation of the role of the Rac1/c-Jun NH2-terminal kinase (JNK) pathway.

Main Results:

  • GDNF treatment induced a significant G2/M cell cycle delay in SK-N-MC cells.
  • This delay was associated with increased Cdc2 phosphorylation, prolonged Cdc2 activity, and stabilized expression of cyclin B1 and Wee1 kinase.
  • The Rac1/c-Jun NH2-terminal kinase (JNK) pathway was identified as a key regulator of Cdc2, cyclin B1, and Wee1 in response to GDNF.
  • GDNF also induced actin reorganization, and the G2/M delay appeared to prevent mitotic progression in cells with disrupted actin.

Conclusions:

  • GDNF induces a G2/M cell cycle delay in RET-expressing neuroectodermal tumor cells.
  • The Rac1/JNK pathway mediates GDNF's effects on cell cycle regulators (Cdc2, cyclin B1, Wee1).
  • GDNF-induced G2/M delay may serve as a protective mechanism against mitotic errors in cells with cytoskeletal abnormalities.

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