THE CASPASE-3 PRECURSOR HAS A CYTOSOLIC AND MITOCHONDRIAL DISTRIBUTION - IMPLICATIONS FOR APOPTOTIC SIGNALING

Caspase-3-mediated proteolysis is a critical element of the apoptotic process. Recent studies have demonstrated a central role for mitochond rial proteins (e.g., Bcl-2 and cytochrome c) in the activation of casp ase-3, by a process that involves interaction of several protein molec ules. Using antibodies that specifically recognize the precursor form of caspase-3, we demonstrate that the caspase-3 proenzyme has a mitoch ondrial and cytosolic distribution in nonapoptotic cells. The mitochon drial caspase-3 precursor is contained in the intermembrane space. Del ivery of a variety of apoptotic stimuli is accompanied by loss of mito chondrial caspase-3 precursor staining and appearance of caspase-3 pro teolytic activity. We propose that the mitochondrial subpopulation of caspase-3 precursor molecules is coupled to a distinct subset of apopt otic signaling pathways that are Bcl-2 sensitive and that are transduc ed through multiple mitochondrion-specific protein interactions.