Synthetic activation of caspases: Artificial death switches

Rebecca A. MacCorkle, Kevin W. Freeman, David M. Spencer

Research output: Contribution to journalArticle

169 Scopus citations

Abstract

The development of safe vectors for gene therapy requires fall-safe mechanisms to terminate therapy or remove genetically altered cells. The ideal 'suicide switch' would be nonimmunogenic and nontoxic when uninduced and able to trigger cell death independent of tissue type or cell cycle stage. By using chemically induced dimerization, we have developed powerful death switches based on the cysteine proteases, caspase-1 ICE (interleukin- 1β converting enzyme) and caspase-3 YAMA. In both cases, aggregation of the target protein is achieved by a nontoxic lipid-permeable dimeric FK506 analog that binds to the attached FK506-binding proteins, FKBPs. We find that intracellular cross-linking of caspase-1 or caspase-3 is sufficient to trigger rapid apoptosis in a Bcl-x(L)-independent manner, suggesting that these conditional proapoptotic molecules can bypass intracellular checkpoint genes, such as Bcl-x(L), that limit apoptosis. Because these chimeric molecules are derived from autologous proteins, they should be nonimmunogenic and thus ideal for long-lived gene therapy vectors. These properties should also make chemically induced apoptosis useful for developmental studies, for treating hyperproliferative disorders, and for developing animal models to a wide variety of diseases.

Original languageEnglish (US)
Pages (from-to)3655-3660
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number7
DOIs
StatePublished - Mar 31 1998

ASJC Scopus subject areas

  • Genetics
  • General

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