The effector phase of physiological cell death relies exclusively on the posttranslational activation of resident components

Sandra H. Chang, Marija Cvetanovic, Kevin J. Harvey, Akira Komoriya, Beverly Z. Packard, David S. Ucker

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15-30
Number of pages16
JournalExperimental Cell Research
Volume277
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to Jurg Tschopp and to Alex Mankin for kindly providing the human FLIP (long) cDNA clone and the translation inhibitors anisomycin and pactamycin, respectively. We thank our colleagues Dunja Lukovic, Alex Mankin, and William Walden for their constructive comments. This work was supported by grants to D.S.U. from the National Institutes of Health.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • Apoptosis
  • Caspases
  • Cdk2
  • Cyclin A
  • Macromolecular synthesis
  • Physiological cell death
  • Post-translational modification
  • Programmed cell death

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