Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells.

Säftig, Paul; Hetman, Michał; Schmahl, Wolfgang W.; Weber, Kris L.; Heine, Lutz; Mossmann, Horst; Köster, Anja; Hess, Barbara; Evers, Meike; Figura, Kurt Von

doi:10.1002/j.1460-2075.1995.tb00029.x

Cited by 401 publications

(374 citation statements)

References 49 publications

(46 reference statements)

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“…Indeed, experiments using cathepsin gene knockout and cathepsin inhibitors demonstrated the redundancy of proteolytic enzymes in the lysosomal apparatus so that overall protein turnover is not affected by single-cathepsin deficiency. 11,12 In neuronal cells, besides a role in intracellular protein turnover, the endosomal system provides a unique pathway to metabolize internalized extracellular nutrients and trophic factors that are essential for their survival. 13 We therefore tested the hypothesis that neither cathepsin is dispensable in nervous system-derived tumors.…”

Section: Abstract: Apoptosis; Neuroblastoma; Caspases; Cathepsins; Pmentioning

confidence: 99%

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Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Castino¹,

Pace²,

Démoz³

et al. 2001

Intl Journal of Cancer

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Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomallysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen. © 2002 Wiley-Liss, Inc. Key words: apoptosis; neuroblastoma; caspases; cathepsins; protease inhibitorsAltered regulation of cell survival and death, including apoptosis, is considered an important factor in tumor development and progression, as well as in the response to antineoplastic therapy. 1,2 The molecular pathways controlling apoptosis include a complex network of intracellular proteases that act in an orderly sequence on cellular substrates and lead to characteristic modifications of cell morphology with eventual DNA cleavage and apoptotic body formation. Several proteolytic systems have been shown to participate in the apoptotic process, depending on the cell type and stimuli adopted. With few exceptions, the caspase system seems to be the most universally involved one. 3,4 Recently, proteases resident within the endosomal-lysosomal compartment (cathepsins) have also been associated with apoptosis. 5-9 These studies demonstrated the need for a cathepsin-mediated proteolytic event in the apoptotic pathway triggered by cytokines or antiblastic drugs. In addition, the active participation of the autophagic proteolytic pathway, particularly of lysosomal cathepsins B and D (CB, CD), has been envisaged in rat pheochromocytoma PC12 cell death after nutrient and serum factor deprivation. In this model of caspasedependent apoptosis, CD acted as a death factor, whereas CB acted as a pro-survival factor. 10 We followed an opposite approach, assuming that the endosomal-lysosomal proteolytic pathway serves crucial functions for cell viability. Indeed, experiments usi...

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Section: Abstract: Apoptosis; Neuroblastoma; Caspases; Cathepsins; Pmentioning

confidence: 99%

“…NB cell lines, GILIN and LAN-5, 11 were grown in a 5% CO 2 atmosphere in RPMI-1640 medium supplemented with 10% heatinactivated FCS, 4 mM glutamine and penicillin/streptomycin mix (1%). Culture reagents were purchased from Sigma (St. Louis, MO).…”

Section: Cell Cultures and Treatmentsmentioning

confidence: 99%

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Castino¹,

Pace²,

Démoz³

et al. 2001

Intl Journal of Cancer

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“…The M3 murine lymphoma cell line expressing temperature-sensitive p53 has been described (Wang et al, 1993). CD +/+ and CD 7 / 7 ®broblasts were isolated and cultured as previously described (Saftig et al, 1995). Transfections were carried out as previously described (Zeng et al, 1997).…”

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

“…A full-length (2.0 kb) human CD cDNA probe was generated by digestion of the pZL-CD clone with EcoRI. A 600 bp mouse CD genomic probe covering exons 7 and 8 was generated by digesting plasmid pCD12 (Saftig et al, 1995) with XbaI and BamHI. A 2.0 kb mouse-p21 probe was generated by digestion of pZL-mouse-WAF1 with EcoRI.…”

Section: Northern and Western Blottingmentioning

confidence: 99%

Potential role for Cathepsin D in p53-dependent tumor suppression and chemosensitivity

Säftig²,

et al. 1998

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Cathepsin D (CD), the major intracellular aspartyl protease, is a mediator of IFN-g and TNF-a induced apoptosis. Using subtractive hybridization screening we isolated CD as an upregulated transcript in PA1 human ovarian cancer cells undergoing adriamycin-induced apoptosis. CD mRNA levels increased in wild-type p53-expressing PA1, ML1 leukemia and U1752 lung cancer cells but not in mutant p53-expressing cells following adriamycin exposure. Overexpression of CD inhibited growth of colon, liver, and ovarian cancer cells. CD protein expression was increased by exposure of ML1 cells to etoposide, adriamycin or g-radiation. Inhibition of CD protease with Pepstatin A suppressed p53-dependent apoptosis in lymphoid cells, suggesting a possible role for CD in p53-dependent cell death. CD 7/7 ®broblasts were found to be more resistant to killing by adriamycin and etoposide, as compared to CD +/+ cells. Two p53 DNA-binding sites located in the CD-promoter speci®cally bound to p53 protein in vitro and appeared to mediate transactivation of a CDpromoter luciferase-reporter during p53-dependent apoptosis. These observations link CD protease to p53-dependent tumor suppression and chemosensitivity.

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“…It is also found in extralysosomal sites, such as the cytosol, plasma membrane, and pericellular spaces, where it participates in several cell processes including cancer metastasis and inflammation Hentze et al, 2003;Roshy et al, 2003). The major function of cathepsin D is the digestion of peptides and proteins within the acidic compartment of lysosomes (Dean, 1975), although it contributes to other physiological roles, such as hormone and antigen processing (Mizuochi et al, 1994;Authier et al, 1995), cell proliferation, and tissue renewal (Saftig et al, 1995), or cell differentiation (Jane et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

Bejarano-Escobar

Holguín-Arévalo

Montero

et al. 2011

Developmental Dynamics

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Here, we show a detailed chronotopographical analysis of cathepsin B and D expression during development of the mouse visual system. Both proteases were detected in large rounded/ameboid cells usually located in close relationship with prominent sites of extensive physiological cell death. In concordance with their morphological features and topographical distribution, we demonstrate that expressing cells corresponded with macrophages and microglial precursors. We found that as microglial precursors differentiated the expression of both cathepsins was down-regulated. Of interest, cathepsin B and D transcripts were never observed in degenerating cells. Our findings point to a role for cathepsin D and B in cell debris degradation after apoptotic processes rather than promoting cell death, as proposed for other developmental models. Additionally their pattern of expression suggests a role in the maturation of the microglial precursors.

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Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells.

Cited by 401 publications

References 49 publications

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Potential role for Cathepsin D in p53-dependent tumor suppression and chemosensitivity

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

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