Characterization of a novel isoform of capase-9 that inhibits apoptosis

We have identified a novel isoform of rat caspase-9 in which the C terminus of full-length caspase-9 is replaced with an alternative peptide sequence. Casp-9-CTD (where CTD is carboxyl-terminal divergent) is expressed in mult iple tissues, with the relative highest expression observed in ovary and he art. Casp-9-CTD was found primarily in the cytoplasm and was not detected i n the nucleus. Structural predictions suggest that in contrast to full-leng th caspase-9, casp-9-CTD will not be processed. Our model is supported by r educed protease activity of casp-9-CTD preparations in vitro and by the lac k of detectable processing of casp-9-CTD proenzyme or the induction of cell death following transfection into cells. Both neuronal and non-neuronal ce ll types transfected with casp-9-CTD were resistant to death evoked by trop hic factor deprivation or DNA damage. In addition, cytosolic lysates prepar ed from cells permanently expressing exogenous casp-9-CTD were resistant to caspase induction by cytochrome c in reconstitution assays. Taken together , our observations indicate that casp-9-CTD acts as a dominant-negative var iant. Its expression in various tissues indicates a physiological role in r egulating cell death.