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© The Rockefeller University Press, 0021-9525/1998//1485 $5.00
The Journal of Cell Biology, Volume 140, Number 6, , 1998 1485-1495

Article

The Caspase-3 Precursor Has a Cytosolic and Mitochondrial Distribution: Implications for Apoptotic Signaling



Marie Mancini*, Donald W. Nicholson, Sophie Roy, Nancy A. Thornberry**, Erin P. Peterson**, Livia A. Casciola-Rosen{ddagger},§, and Antony Rosen*,§,||

* Department of Medicine, {ddagger} Department of Dermatology, § Department of Cell Biology and Anatomy, || Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Pointe Claire-Dorval, Quebec, H9R 4P8, Canada; and ** Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065

Caspase-3–mediated proteolysis is a critical element of the apoptotic process. Recent studies have demonstrated a central role for mitochondrial proteins (e.g., Bcl-2 and cytochrome c) in the activation of caspase-3, by a process that involves interaction of several protein molecules. Using antibodies that specifically recognize the precursor form of caspase-3, we demonstrate that the caspase-3 proenzyme has a mitochondrial and cytosolic distribution in nonapoptotic cells. The mitochondrial caspase-3 precursor is contained in the intermembrane space. Delivery of a variety of apoptotic stimuli is accompanied by loss of mitochondrial caspase-3 precursor staining and appearance of caspase-3 proteolytic activity. We propose that the mitochondrial subpopulation of caspase-3 precursor molecules is coupled to a distinct subset of apoptotic signaling pathways that are Bcl-2 sensitive and that are transduced through multiple mitochondrion-specific protein interactions.

Abbreviations used in this paper: AIF, apoptosis-inducing factor; CHAPS, 3-([3-cholamidopropyl]-dimethyllammonio)-1-propanesulfonate; DAPI, 4',6-diamidino-2-phenylindole; DFF, DNA fragmentation factor; ECL, enhanced chemiluminescence; HUVEC, human umbilical vein endothelial cells; KGM, keratinocyte growth medium; KRB, Krebs' Ringers buffer; PARP, poly (ADP-ribose) polymerase.

Address all correspondence to Antony Rosen, Johns Hopkins University School of Medicine, 720 Rutland Ave., Room 1055, Baltimore, MD 21205. Tel.: (410) 955-0139. Fax: (410) 955-0964. E-mail: arosen{at}welchlink.welch.jhu.edu


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