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

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• De novo macromolecular synthesis was thought essential for physiological cell death.
• Transcription and translation inhibitors can both prevent and induce cell death.
• A conserved pathway involving caspases and cyclin-dependent kinases mediates physiological cell death.

Purpose of the Study:

• To investigate the role of de novo macromolecular synthesis in cell death.
• To elucidate the mechanism by which transcription/translation inhibitors affect cell death.
• To determine the relationship between inhibitor-induced cell death and the physiological cell death pathway.

Main Methods:

• Utilized transcription and translation inhibitors at varying concentrations.
• Mapped the sequence of events in physiological and inhibitor-induced cell death.
• Assessed the activation of caspases and cyclin-dependent kinases.
• Investigated cytochrome c release and the effect of Bcl-2 overexpression.

Main Results:

• Inhibitors blocking cell death act upstream, preventing pathway activation.
• High inhibitor doses trigger cell death via post-translational activation of existing lethal molecules.
• Inhibitor-induced death involves cytochrome c release, caspase 9 activation, and is Bcl-2 sensitive.
• De novo macromolecular synthesis is only involved in upstream modulatory aspects of cell death.

Conclusions:

• Essential cell death execution molecules are resident within cells and activated post-translationally.
• De novo macromolecular synthesis is not universally required for cell death execution.
• Specific inhibitors modulate cell death pathways upstream, while high doses trigger death via pre-existing machinery.