title: p53 deficiency fails to prevent increased programmed cell death in the Bcl-X(L)-deficient nervous system.
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.
authors.affiliation: Department of Pathology and Immunology Division of Neuropathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Klocke
authors.forename: C B
authors.initials: CB
authors.lastname: Latham
authors.forename: C
authors.initials: C
authors.lastname: D'Sa
authors.forename: K A
authors.initials: KA
authors.lastname: Roth
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D005804:Genes, Lethal / Q000235:genetics; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency* / Q000235:genetics; D013687:Telencephalon / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D051020:bcl-X Protein
chemical_list: D000964:Antimetabolites, Antineoplastic; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C101467:XRCC4 protein, human; D051020:bcl-X Protein; D003561:Cytarabine; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D011088:DNA Ligases; D000072481:DNA Ligase ATP