REGULATED APOPTOSIS USING CHEMICALLY INDUCED DIMERIZATION OF APOPTOSIS FACTORS

摘要

The present invention discloses artificial death switches (ADSs) based on chemically induced dimerization of the cysteine proteases, caspase-1 (ICE) and caspase-3 (YAMA). In both cases, aggregation of the target protein is achieved by a non-toxic, lipid-permeable, dimeric FK506 analog that binds to an attached FK506-binding protein (FKBP). The intracellular crosslinking of caspase-1 or caspase-3 is sufficient to trigger rapid apoptosis in a Bcl-xL-independent manner, suggesting that these conditional pro-apoptotic molecules can bypass intracellular checkpoint genes, like Bcl-xL, that limit apoptosis. Since these chimeric molecules are derived from autologous proteins, they should be non-immunogenic and thus ideal for long-lived gene therapy vectors. These properties should also make chemically-induced apoptosis (CIA) useful for developmental studies, for treating hyperproliferative disorders and for developing animal models to a wide variety of diseases.