title: The effector phase of physiological cell death relies exclusively on the posttranslational activation of resident components.
abstract: Inhibitors of transcription and translation can protect cells from physiological cell deaths induced by a variety of stimuli. These observations have been taken to suggest that de novo macromolecular synthesis may be an essential component of the cell death process. Paradoxically, the same inhibitors, at higher concentrations, themselves trigger the death of cells. Previously, we have mapped a conserved and ordered sequence of events that exerts physiological cell death. Diverse signals converge to activate this lethal pathway, composed of a proteolytic cascade of caspases and subsequent cyclin-dependent kinases. Here we report that inhibitors of nuclear gene expression, when they block cell death, act upstream of this lethal process to prevent its activation. In contrast, when cell death is triggered by high doses of the inhibitors, these same essential molecules are activated, despite the essentially complete blockade of macromolecular synthesis. This inhibitor-induced death response is associated with the release of cytochrome c from mitochondria and the activation of apical caspase 9 and is blocked by overexpression of Bcl-2. These data demonstrate that all essential molecules that exert lethality already are resident within cells and are activated posttranslationally upon stimulation. De novo macromolecular synthesis pertains idiosyncratically only to upstream, modulatory elements of particular death responses.
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine, Rm. E803 (M/C 790), 835 South Wolcott, Chicago 60612, USA.
authors.forename: Sandra H
authors.initials: SH
authors.lastname: Chang
authors.forename: Marija
authors.initials: M
authors.lastname: Cvetanovic
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harvey
authors.forename: Akira
authors.initials: A
authors.lastname: Komoriya
authors.forename: Beverly Z
authors.initials: BZ
authors.lastname: Packard
authors.forename: David S
authors.initials: DS
authors.lastname: Ucker
mesh_terms: D017209:Apoptosis; D042846:CDC2-CDC28 Kinases; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances; D008928:Mitochondria / Q000187:drug effects; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
chemical_list: D019925:Cyclin A; D003574:Cytochrome c Group; D005938:Glucocorticoids; D046911:Macromolecular Substances; D011500:Protein Synthesis Inhibitors; D003609:Dactinomycin; D012313:RNA; D003907:Dexamethasone; D003513:Cycloheximide; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases