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Endosomal-Lysosomal Proteolysis Mediates Death Signalling by TNFα, Not by Etoposide, in L929 Fibrosarcoma Cells: Evidence for an Active Role of Cathepsin D
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M. Démoz
Published/Copyright:
June 1, 2005
Abstract
In several in vitro models of apoptosis, lysosomal proteolysis has been shown to play an active role in mediating the death signal by cytokines or antiblastic drugs. Depending on the experimental cell model and the cytotoxic stimulus applied, an increased expression and the cytosolic translocation of either cathepsin D or B have been reported in apoptotic cells. We have analysed the involvement of these lysosomal proteases in a canonical apoptotic cell model, namely L929 fibroblasts, in which apoptosis was induced by cytotoxic agents acting through different mechanisms: (i) the cytokine TNFα, which triggers the cell suicide via interaction with its membrane receptor, and (ii) the topoisomerase IIinhibitor etoposide (VP16), which directly causes DNA damage. In both cases the activity of cathepsins B and D increased in apoptosing cultures. CA074-Me, a specific inhibitor of cathepsin B, and Leupeptin, a broad inhibitor of serine and cysteine proteases (among which is cathepsin B), did not exert any protection from TNFα. In contrast, preloading the cells with pepstatin A, a specific inhibitor of cathepsin D, protected L929 cells from TNFα cytotoxicity by more than 50%. However, no protection was observed if pepstatin A was added concomitantly with the cytokine. Inhibition of either cathepsin B or D did not impede apoptosis induced by etoposide. Lysosomal integrity was preserved and cathepsin D remained still confined in vesicular structures in apoptotic cells treated with either TNFα or etoposide. It follows that proteolysis by cathepsin D is likely to represent an early event in the death pathway triggered by TNFα and occurs within the endosomal lysosomal compartment.
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Published Online: 2005-06-01
Published in Print: 2002-08-27
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
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- Proteases and Their Inhibitors: Traditional Research Subjects in the Munich Area
- Apoptotic Pathways: Involvement of Lysosomal Proteases
- Human Tissue Kallikreins: A New Enzymatic Cascade Pathway?
- Discovery of Chemokine Substrates for Matrix Metalloproteinases by Exosite Scanning: A New Tool for Degradomics
- Novel Secretory Vesicle Serpins, Endopin 1 and Endopin 2: Endogenous Protease Inhibitors with Distinct Target Protease Specificities
- Extracellular Proteases of Staphylococcus spp.
- Secreted Aspartic Proteases as Virulence Factors of Candida Species
- Triple-Helical Peptide Analysis of Collagenolytic Protease Activity
- Phage Display Substrate: A Blind Method for Determining Protease Specificity
- Evolution of Placental Proteases
- Factor VII Activating Protease (FSAP): A Novel Protease in Hemostasis
- Cold-Adapted and Mesophilic Brachyurins
- The Role of Dipeptidyl Peptidase IV (DP IV) Enzymatic Activity in T Cell Activation and Autoimmunity
- Biochemical Features, Molecular Biology and Clinical Relevance of the Human 15-Domain Serine Proteinase Inhibitor LEKTI
- Interaction of Plasminogen Activator Inhibitor Type-1 (PAI-1) with Vitronectin (Vn): Mapping the Binding Sites on PAI-1 and Vn
- Structure-Function Relationship of Bromelain Isoinhibitors from Pineapple Stem
- Structural Basis for the Processive Protein Degradation by Tricorn Protease
- Zinc Ligands in an Astacin Family Metalloprotease Meprin A
- Probing the Active Sites and Mechanisms of Rat Metalloproteases Meprin A and B
- (R)-3-Amidinophenylalanine-Derived Inhibitors of Factor Xa with a Novel Active-Site Binding Mode
- Inhibition of Arginine Gingipains (RgpB and HRgpA) with Benzamidine Inhibitors: Zinc Increases Inhibitory Potency
- Cathepsin B Stability, But Not Activity, Is Affected in Cysteine:Cystine Redox Buffers
- Inhibition of Mammalian Legumain by Michael Acceptors and AzaAsn-Halomethylketones
- Role of the Prosegment of Fasciola hepatica Cathepsin L1 in Folding of the Catalytic Domain
- Roles for Arg- and Lys-Gingipains in the Disruption of Cytokine Responses and Loss of Viability of Human Endothelial Cells by Porphyromonas gingivalis Infection
- Aberrant Expression of Serpin Squamous Cell Carcinoma Antigen 2 in Human Tumor Tissues and Cell Lines: Evidence of Protection from Tumor Necrosis Factor-Mediated Apoptosis
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- Identification of a Signal Transduction Pathway That Regulates MMP-9 mRNA Expression in Glomerular Injury
- Modulation of the Endosomal and Lysosomal Distribution of Cathepsins B, L and S in Human Monocytes/Macrophages
- Characterization of Novel Anti-Cathepsin W Antibodies and Cellular Distribution of Cathepsin W in the Gastrointestinal Tract
- Functional Consequences of Cathepsin L Deficiency in Human Lung Epithelial Cells
- Determination of Cathepsin B Expression May Offer Additional Prognostic Information for Ovarian Cancer Patients
- CA-074, But Not Its Methyl Ester CA-074Me, Is a Selective Inhibitor of Cathepsin B within Living Cells
- Trypsin Mutants for Structure-Based Drug Design: Expression, Refolding and Crystallisation
