title: The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.
abstract: The p53 protein is a critical participant in a signal transduction pathway which mediates a G1 cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder, ataxia-telangiectasia (AT), exhibit suboptimal (delayed and/or defective) induction of p53 protein after ionizing radiation with some dependence on dose. Other protein products which participate in this signal transduction pathway, including p21WAF1/CIP1, Gadd45, and Mdm2, are also suboptimally induced in AT cells after ionizing radiation. Induction of p53 is also abnormal in AT cells following treatment with methylmethanesulfonate and bleomycin but appears relatively normal following treatment with UV-C irradiation or the topoisomerase inhibitors, etoposide and camptothecin. These results demonstrate a specific defect in this p53-dependent signal transduction pathway in AT cells. Potential models for this observed specificity of the AT defect as measured by p53 induction include problems with responses to: (a) single-strand, but not double-strand, DNA breaks; or (b) chemically, but not enzymatically, generated DNA ends.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, Maryland 21287.
authors.forename: C E
authors.initials: CE
authors.lastname: Canman
authors.forename: A C
authors.initials: AC
authors.lastname: Wolff
authors.forename: C Y
authors.initials: CY
authors.lastname: Chen
authors.forename: A J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: M B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D016193:G1 Phase; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D008741:Methyl Methanesulfonate