The course of etoposide-induced apoptosis in Jurkat cells lacking p53 and Bax.
Jurkat T-lymphocytes lack p53 and Bax but contain p73 and Bid and are killed by etoposide (ETO). With ETO c-abl is phosphorylated and phosphorylated p73 increased. Translocation of full-length Bid to mitochondria follows, with induction of the mitochondrial permeability transition (MPT) and release of cytochrome c into the cytosol. Pronounced swelling of mitochondria was evident ultrastructurally, and the MPT inhibitor cyclosporin A prevented the release of cytochrome c. Overexpression of Bcl-2 prevented the translocation of Bid, the release of cytochrome c, and cell death. The pan-caspase inhibitor ZVAD-FMK prevented the cell killing, but not the initial release of cytochrome c. An accumulation of tBid occurred at later times in association with Bid degradation. A sequence is proposed that couples DNA damage to Bid translocation via activation of c-abl and p73. Bid translocation induces the MPT, the event that causes release of cytochrome c, activation of caspases, and cell death.
Karpinich
Natalie O
NO
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
Tafani
Marco
M
Schneider
Timothy
T
Russo
Matteo A
MA
Farber
John L
JL
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000737:chemistry / Q000502:physiology / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000737:chemistry / Q000473:pathology* / Q000502:physiology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D000972:Antineoplastic Agents, Phytogenic; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D061945:Caspase Inhibitors; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D005047:Etoposide; D016572:Cyclosporine; D045304:Cytochromes c; D016315:Proto-Oncogene Proteins c-abl; D020169:Caspases