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A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia

M B Kastan1, Q Zhan, W S el-Deiry

  • 1Johns Hopkins Oncology Center, Baltimore, Maryland 21287.

Cell
|November 23, 1992
PubMed

Insights

Disrupting cell cycle checkpoints, like those involving p53 and GADD45, impairs DNA damage response. This pathway is crucial for cell survival and preventing mutations, with defects potentially leading to cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cell cycle checkpoints are vital for maintaining genomic stability after DNA damage.
  • Ionizing radiation (IR) can trigger cell cycle arrest to allow for DNA repair.
  • Defects in DNA damage response pathways are linked to cancer predisposition and radiosensitivity.

Purpose of the Study:

  • To investigate the role of p53 and GADD45 in the G1 cell cycle checkpoint response to IR.
  • To identify key components of the DNA damage-induced signal transduction pathway.
  • To explore the link between pathway abnormalities and cancer development.

Main Methods:

  • Disruption of wild-type p53 alleles in murine fibroblasts.
  • Analysis of p53 protein levels in cells from ataxia-telangiectasia (AT) patients.
  • Assessing IR-induced GADD45 gene expression.
  • Electrophoretic mobility shift assays to study p53-DNA binding.

Main Results:

  • Disruption of p53 abolished the IR-induced G1 checkpoint in murine fibroblasts.
  • AT cells showed defective IR-induced p53 accumulation and GADD45 induction.
  • Wild-type p53 directly bound to a conserved element in the GADD45 gene promoter.
  • A p53-dependent nuclear factor binding to GADD45 was identified in irradiated cells.

Conclusions:

  • A signal transduction pathway involving AT gene(s), p53, and GADD45 mediates cell cycle arrest after DNA damage.
  • Abnormalities in this pathway contribute to radiosensitivity and likely cancer development.
  • p53 plays a critical role in regulating GADD45 expression and cell cycle control following IR.

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