p53 deficiency fails to prevent increased programmed cell death in the Bcl-X(L)-deficient nervous system

Cell Death Differ. 2002 Oct;9(10):1063-8. doi: 10.1038/sj.cdd.4401067.

Abstract

Bcl-X(L) mice display a similar neurodevelopmental phenotype as rb, DNA ligase IV, and XRCC4 mutant embryos, suggesting that endogenous Bcl-X(L) expression may protect immature neurons from death caused by DNA damage and/or cell cycle dysregulation. To test this hypothesis, we generated bcl-x/p53 double mutants and examined neuronal cell death in vivo and in vitro. Bcl-X(L)-deficient primary telencephalic neuron cultures were highly susceptible to the apoptotic effects of cytosine arabinoside (AraC), a known genotoxic agent. In contrast, neurons lacking p53, or both Bcl-X(L) and p53, were markedly, and equivalently, resistant to AraC-induced caspase-3 activation and death in vitro indicating that Bcl-X(L) lies downstream of p53 in DNA damage-induced neuronal death. Despite the ability of p53 deficiency to protect Bcl-X(L)-deficient neurons from DNA damage-induced apoptosis in vitro, p53 deficiency had no effect on the increased caspase-3 activation and neuronal cell death observed in the developing Bcl-X(L)-deficient nervous system. These findings suggest that Bcl-X(L) expression in the developing nervous system critically regulates neuronal responsiveness to an apoptotic stimulus other than inadequate DNA repair or cell cycle abnormalities.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3
  • Caspases / metabolism
  • Cells, Cultured
  • Cytarabine / pharmacology
  • DNA Ligase ATP
  • DNA Ligases / genetics
  • DNA Ligases / metabolism
  • DNA Repair / drug effects
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Fetus
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics*
  • Genes, Lethal / genetics
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / deficiency*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Telencephalon / cytology
  • Telencephalon / embryology*
  • Telencephalon / metabolism*
  • Tumor Suppressor Protein p53 / deficiency*
  • Tumor Suppressor Protein p53 / genetics
  • bcl-X Protein

Substances

  • Antimetabolites, Antineoplastic
  • Bcl2l1 protein, mouse
  • DNA-Binding Proteins
  • LIG4 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • XRCC4 protein, human
  • bcl-X Protein
  • Cytarabine
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • DNA Ligases
  • DNA Ligase ATP