Targeted cell killing by reconstituted caspases

Proceedings of the National Academy of Sciences of the United States of America
Dattananda Chelur, Martin Chalfie

Abstract

We have developed a two-component system involving reconstituted caspase (recCaspase) for selective and/or conditional ablation of targeted cells. Caspases, the executioners of programmed cell death, are normally synthesized as inactive zymogens and are activated by proteolytic processing of their subunits. We show here, using two different caspases, Caenorhabditis elegans CED-3 and human Caspase-3, that coexpression of the subunits generates constitutively active caspase activity that leads to cell death. This recCaspase activity, however, occurred only when the subunits associated through binding of linked antiparallel leucine-zipper domains. We exploited the dual-component nature of recCaspases by expressing the individual subunits from combinations of promoters either to target selectively the subset of cells for apoptosis or induce cell death in specific cells at specific times during development. The high degree of target specificity and tight regulation of induction of recCaspase would be advantageous in creating animal models that are ablated for specific cells and in other targeted cell killings.

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Related Concepts

Ced-3 protein, C elegans
Neurons
Early Promoters, Genetic
Protein Conformation
Proteins, Recombinant DNA
Substrate Specificity
Cell Death
Caenorhabditis elegans
Apoptosis, Intrinsic Pathway
Caspase

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