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Wild-type p53 can induce p21 and apoptosis in neuroblastoma cells but the DNA damage-induced G1 checkpoint function

P P McKenzie1, S M Guichard, D S Middlemas

  • 1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 13, 2000
PubMed

Insights

Neuroblastoma cells express nuclear p53, which can be induced by DNA damage. However, these cells show impaired G1 cell cycle arrest, suggesting a nonfunctional downstream pathway despite functional apoptosis induction.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • p53 is a crucial tumor suppressor protein regulating apoptosis.
  • Nuclear localization of p53 is essential for its function as a transcription factor.
  • Cytoplasmic sequestration of p53 is a proposed mechanism for its suppression, especially in neuroblastoma with low p53 mutation rates.

Purpose of the Study:

  • To investigate the expression and activity of p53 in neuroblastoma cells.
  • To determine the functionality of the DNA damage response pathway downstream of p53 in neuroblastoma.
  • To elucidate the role of p53 in G1 cell cycle arrest and apoptosis in neuroblastoma.

Main Methods:

  • Analysis of nuclear p53 protein expression in neuroblastoma cell lines.
  • Induction of DNA damage using ionizing radiation (10-Gy) and chemotherapy (IC80).
  • Adenoviral vector transduction to express exogenous wild-type p53.
  • Assessment of p53 and p21 induction, G1 cell cycle arrest, and apoptosis.

Main Results:

  • Nuclear p53 expression was observed in neuroblastoma cell lines.
  • DNA damage induced both p53 and p21, but G1 cell cycle arrest was attenuated.
  • Exogenous p53 expression also induced p21 but failed to enhance G1 arrest, indicating a downstream defect.
  • p53-mediated apoptosis induction remained functional in these cells.

Conclusions:

  • Neuroblastoma cells express nuclear p53, which can be transcriptionally activated by DNA damage.
  • The DNA damage-induced G1 cell cycle arrest pathway downstream of p53 is attenuated or nonfunctional in neuroblastoma.
  • Despite impaired G1 arrest, p53 retains its ability to induce apoptosis, correlating with the chemosensitive phenotype of neuroblastoma.

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