Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis

Alternatively spliced isoforms of certain apoptosis regulators, such as Bcl -x, Ced-4, and Ich-1, have been shown to play opposing roles in regulating apoptosis, Here, we describe the identification of an endogenous alternativ ely spliced isoform of caspase-9, named caspase-9b, which lacks the central large subunit caspase domain. Caspase-9b is detectable in many cell lines by PCR and at the mRNA and protein levels. Caspase-9b can interact with the caspase recruitment domain of Apaf-1, and like the active site mutant of c aspase-9, it can inhibit multiple forms of apoptosis, including those trigg ered by oligomerization of death receptors. It can also block activation of caspase-9 and -3 by Apaf-1 in an in vitro cytochrome c-dependent caspase a ctivation assay. These results suggest that caspase-9b functions as an endo genous apoptosis inhibitory molecule by interfering with the formation of a functional Apaf-1-caspase-9 complex.