Different Subcellular Distribution of Caspase-3 and Caspase-7 following Fas-induced Apoptosis in Mouse Liver

Abstract

Caspases plays a key role in the execution phase of apoptosis. "Initiator" caspases, such as caspase-8, activate "effector" caspases, such as caspase-3 and -7, which subsequently cleave cellular substrates thereby precipitating the dramatic morphological changes of apoptosis. Following treatment of mice with an agonistic antiFas antibody to induce massive hepatocyte apoptosis, we now demonstrate a distinct subcellular localization of the effector caspases-3 and -7. Active caspase-3 is confined primarily to the cytosol, whereas active caspase-7 is associated almost exclusively with the mitochondrial and microsomal fractions. These data suggest that caspases-3 and -7 exert their primary functions in different cellular compartments and offer a possible explanation of the presence of caspase homologs with overlapping substrate specificities. Translocation and activation of caspase-7 to the endoplasmic reticulum correlates with the proteolytic cleavage of the endoplasmic reticular-specific substrate, sterol regulatory element-binding protein 1. Liver damage, induction of apoptosis, activation and translocation of caspase-7, and proteolysis of sterol regulatory element-binding protein 1 are all blocked by the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD.fmk). Our data demonstrate for the first time the differential subcellular compartmentalization of specific effector caspases following the induction of apoptosis in vivo.

The effect of sea anemone (H. magnifica) venom on two human breast cancer lines: death by apoptosis

“…The intrinsic and extrinsic apoptosis pathways converge with the activation of caspase-3 and subsequently other executioner caspases and nucleases drive the terminal events of programmed cell death (MacFarlane 2003;Crow et al 2004;Prunell et al 2005;Elmore 2007;Pizon et al 2011). Activated initiator caspases can cleave and activate effector caspases such as caspase-3, which in turn cleaves a variety of cellular substrates (Chandler et al 1998). H. magnifica venom extract cleaved caspase-8, caspase-9 and activated caspase-3 as detected using luminescence assays.…”

Involvement of caspase 3-activated DNase in internucleosomal DNA cleavage induced by diverse apoptotic stimuli

“…On the other hand, a cell line (MCF-7) lacking caspase-3, and thymocytes and splenocytes from caspase-3-null mice do not show DNA fragmentation upon treatment with apoptotic stimuli (Janicke et al, 1998; Tang and Kidd, 1998; Woo et al, 1998). Recent analysis of the subcellular localization of caspase-3 and caspase-7 has indicated that the active caspase-3 is primarily localized in the cytosol, whereas active caspase-7 is in the microsomal and mitochondria fractions (Chandler et al, 1998). This di erent subcellular distribution of caspases 3 and 7 may explain why the cells lacking caspase-3 do not undergo DNA fragmentation after apoptotic stimuli.…”

Cell Death-Associated Translocation of Plasma Membrane Components Induced by CTL

“…Fas-induced translocation may reflect the stimulated endocytosis of membrane-associated FM1-43 following multimerization of complexes consisting of Fas, adaptor proteins, and procaspases. The internalized caspases may then be targeted to sites where executioner caspases are sequestered, leading to activation of executioner caspases (37,38). Caspase activation is also implicated in the cell-surface expression of PS, another indication of apoptotic cell death, by the analysis with caspase inhibitors (32).…”