title: Activation of p53/ATM-dependent DNA damage signaling pathway by shiga toxin in mammalian cells.
abstract: In this report, we studied the role of DNA damage signaling pathway in shiga toxin (STX)-induced mammalian cell death. Shiga toxin 1 exhibited cytotoxic activity in different mammalian cells such as HeLa cells, mouse embryo fibroblasts, and Caco-2 cells (a human intestinal primary fibroblast cell line). STX-1 was found to induce the release of cytochrome c from the mitochondria, nuclear condensation, and fragmentation of chromosomal DNA. STX-1 activated DNA damage signaling as determined by induction of H2AX phosphorylation and cleavage of PARP. Inhibition of caspase-3 reduced STX-1-induced phosphorylation of H2AX and nuclear condensation. It was also found that STX-1-induced p53 expression, and activated ATM in mammalian cells. STX-1-induced nuclear condensation significantly reduced in p53-, and ATM-knockout cells suggesting an involvement of p53 and ATM in transducing signals produced by STX in inducing apoptosis in mammalian cells. This is the first demonstration of involvement of ATM/p53 in STX-inducing mammalian cell death.
authors.affiliation: ICDDR, B: Centre for Health and Population Research, GPO Box-128, Dhaka 1000, Bangladesh.
authors.forename: Kaisar A
authors.initials: KA
authors.lastname: Talukder
authors.forename: Ishrat J
authors.initials: IJ
authors.lastname: Azmi
authors.forename: K Ahtesham
authors.initials: KA
authors.lastname: Ahmed
authors.forename: M Sabir
authors.initials: MS
authors.lastname: Hossain
authors.forename: Yearul
authors.initials: Y
authors.lastname: Kabir
authors.forename: Alejandro
authors.initials: A
authors.lastname: Cravioto
authors.forename: David A
authors.initials: DA
authors.lastname: Sack
authors.forename: Alam
authors.initials: A
authors.lastname: Nur-E-Kamal
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D002875:Chromosomes / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry; D004249:DNA Damage; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D022622:Shiga Toxin 1 / Q000633:toxicity*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D022622:Shiga Toxin 1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases