The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
F. Morle - One of the best experts on this subject based on the ideXlab platform.
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Caspase cleavage of the transcription factor FLI-1 during preB leukemic cell death.
BBA - Biochimica et Biophysica Acta, 2002Co-Authors: S. Sarrazin, Christelle Bonod-bidaud, P. Remy, P. Mehlen, F. MorleAbstract:Programmed cell death (apoptosis) is a complex phenomenon that is mediated in mammals mainly via the selective cleavage of intracellular proteins by the large family of cysteine Aspartate Protease caspases. Apoptosis is tightly regulated by the competitive effect of numerous proteins displaying either pro-apoptotic or anti-apoptotic activity. The ETS-family transcription factor FLI-1, frequently associated with malignant transformation, has been shown to display anti-apoptotic activity in several cell types including avian erythroblasts, mouse fibroblasts or lymphoid cells. We show here that apoptosis of murine preB leukemic cells is accompanied with the specific cleavage of FLI-1 by a caspase-like activity. We also demonstrate that the two isoforms of FLI-1 are indeed cleaved at three conserved sites by caspase 3 in vitro. The conservation of these cleavage sites among species suggests that the caspase cleavage of the anti-apoptotic transcription factor FLI-1 may represent a critical step to ensure irreversible cell death.Programmed cell death (apoptosis) is a complex phenomenon that is mediated in mammals mainly via the selective cleavage of intracellular proteins by the large family of cysteine Aspartate Protease caspases. Apoptosis is tightly regulated by the competitive effect of numerous proteins displaying either pro-apoptotic or anti-apoptotic activity. The ETS-family transcription factor FLI-1, frequently associated with malignant transformation, has been shown to display anti-apoptotic activity in several cell types including avian erythroblasts, mouse fibroblasts or lymphoid cells. We show here that apoptosis of murine preB leukemic cells is accompanied with the specific cleavage of FLI-1 by a caspase-like activity. We also demonstrate that the two isoforms of FLI-1 are indeed cleaved at three conserved sites by caspase 3 in vitro. The conservation of these cleavage sites among species suggests that the caspase cleavage of the anti-apoptotic transcription factor FLI-1 may represent a critical step to ensure irreversible cell death.
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Caspase cleavage of the transcription factor FLI-1 during preB leukemic cell death.
Biochimica et Biophysica Acta - Molecular Cell Research, 2002Co-Authors: S. Sarrazin, Christelle Bonod-bidaud, P. Remy, P. Mehlen, F. MorleAbstract:Programmed cell death (apoptosis) is a complex phenomenon that is mediated in mammals mainly via the selective cleavage of intracellular proteins by the large family of cysteine Aspartate Protease caspases. Apoptosis is tightly regulated by the competitive effect of numerous proteins displaying either pro-apoptotic or anti-apoptotic activity. The ETS-family transcription factor FLI-1, frequently associated with malignant transformation, has been shown to display anti-apoptotic activity in several cell types including avian erythroblasts, mouse fibroblasts or lymphoid cells. We show here that apoptosis of murine preB leukemic cells is accompanied with the specific cleavage of FLI-1 by a caspase-like activity. We also demonstrate that the two isoforms of FLI-1 are indeed cleaved at three conserved sites by caspase 3 in vitro. The conservation of these cleavage sites among species suggests that the caspase cleavage of the anti-apoptotic transcription factor FLI-1 may represent a critical step to ensure irreversible cell death.
Yigong Shi - One of the best experts on this subject based on the ideXlab platform.
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Cryo-EM structures of human γ-secretase.
Current opinion in structural biology, 2017Co-Authors: Guanghui Yang, Rui Zhou, Yigong ShiAbstract:γ-secretase, a membrane-embedded Aspartate Protease, catalyzes peptide bond hydrolysis of a large variety of type I integral membrane proteins exemplified by amyloid precursor protein (APP). Cleavage of APP leads to formation of β-amyloid plaque, which is a hallmark of Alzheimer's disease (AD). Over 200 AD-associated mutations are mapped to presenilin 1 (PS1), the catalytic component of γ-secretase. In the past three years, several cryo-electron microscopy (cryo-EM) structures of human γ-secretase have been determined at near atomic resolutions. Here we summarize the methods involved and discuss structural features of γ-secretase and the associated functional insights.
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structure of a presenilin family intramembrane Aspartate Protease
Nature, 2013Co-Authors: Shangyu Dang, Chuangye Yan, Xinqi Gong, Jiawei Wang, Yigong ShiAbstract:Presenilin and signal peptide peptidase (SPP) are intramembrane aspartyl Proteases that regulate important biological functions in eukaryotes. Mechanistic understanding of presenilin and SPP has been hampered by lack of relevant structural information. Here we report the crystal structure of a presenilin/SPP homologue (PSH) from the archaeon Methanoculleus marisnigri JR1. The Protease, comprising nine transmembrane segments (TMs), adopts a previously unreported protein fold. The amino-terminal domain, consisting of TM1–6, forms a horseshoe-shaped structure, surrounding TM7–9 of the carboxy-terminal domain. The two catalytic Aspartate residues are located on the cytoplasmic side of TM6 and TM7, spatially close to each other and approximately 8 A into the lipid membrane surface. Water molecules gain constant access to the catalytic Aspartates through a large cavity between the amino- and carboxy-terminal domains. Structural analysis reveals insights into the presenilin/SPP family of intramembrane Proteases. Presenilin, the catalytic component of γ-secretase, cleaves amyloid precursor protein into short peptides that form the plaques that are found in the brains of patients with Alzheimer’s disease; here the structure of a presenilin homologue is described, which will serve as a framework for understanding the mechanisms of action of presenilin and γ-secretase. Presenilin — the catalytic component of γ-secretase — and signal peptide peptidase are intramembrane aspartyl Proteases that regulate important biological functions in eukaryotes. The most well-known substrate of γ-secretase is amyloid precursor protein which, when cleaved by γ- and β-secretase, produces the short peptide that can form the amyloid plaques in the brains of Alzheimer's disease patients. In this manuscript, the authors report the X-ray crystal structure of a presenilin/signal peptide peptidase homologue, which reveals that the two catalytic Aspartate residues are located approximately 8 A into the lipid membrane surface. This structure will serve as a framework for understanding the mechanisms of action of presenilin, γ-secretase and signal peptide peptidase
Junichi Fujii - One of the best experts on this subject based on the ideXlab platform.
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Inactivation of cysteine and serine Proteases by singlet oxygen
Archives of biochemistry and biophysics, 2007Co-Authors: Daisuke Suto, Kazuaki Sato, Yoshihiro Ohba, Yoshihito Iuchi, Yoshitaka Ikeda, Junichi FujiiAbstract:The reaction of singlet oxygen with individual proteins is less well understood than that with other biological molecules. The inhibition of caspase 3 by singlet oxygen appears to involve the modification of a catalytic cysteine residue, since the reactivity of the sulfhydryl with alkylating agents decreased after singlet oxygen treatment. In addition to three cysteine Proteases, two serine Proteases were also found to be inhibited by singlet oxygen with a similar dose dependency, while an Aspartate Protease and a metalloProtease were not affected. The carbonyl content of these enzymes was elevated as the result of treatment with singlet oxygen. The catalytic center in serine Proteases and cysteine Proteases, in which catalytic reactions are based on similar mechanisms involving nucleophilic catalysis assisted by histidine as a general acid/base, can be expected to be modified by singlet oxygen and undergo inactivation.
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Specific inactivation of cysteine Protease-type cathepsin by singlet oxygen generated from naphthalene endoperoxides.
Biochemical and biophysical research communications, 2005Co-Authors: Yuki Nagaoka, Kaoru Otsu, Futoshi Okada, Kazuaki Sato, Yoshihiro Ohba, Naoki Kotani, Junichi FujiiAbstract:Singlet oxygen is a causal factor in light-induced skin photoaging and the cytotoxic process of tumor cells in photodynamic chemotherapy. To develop a better understanding of the functional consequences of protein modification by singlet oxygen, the effects of naphthalene endoperoxide on lysosomal Protease, cathepsin, were examined. When the soluble fraction of normal human fetal skin fibroblast cells was treated with the endoperoxide, the activities of cysteine Proteases, cathepsins B and L/S, were inhibited, but that of Aspartate Protease, cathepsin D/E, was not. The reduction of the endoperoxide-treated soluble fractions by treatment with dithiothreitol barely recovered the activities. Cathepsin B, purified from normal human liver, exhibited similar profiles to that in cytosol. These data suggest that singlet oxygen oxidatively modifies an amino acid residue essential for catalysis and consequently results in the irreversible inactivation of cysteine Protease-type cathepsin.
Michael Heinrich - One of the best experts on this subject based on the ideXlab platform.
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cathepsin d is involved in the regulation of transglutaminase 1 and epidermal differentiation
Journal of Cell Science, 2004Co-Authors: Friederike Egberts, Marc Wickel, Jensmichael Jensen, Supandi Winotomorbach, Stephan Pfeiffer, Michael Schunck, Judith Steude, Paul Saftig, Michael Heinrich, Ehrhardt ProkschAbstract:We previously demonstrated that the Aspartate Protease cathepsin D is activated by ceramide derived from acid sphingomyelinase. Increased expression of cathepsin D in the skin has been reported in wound healing, psoriasis and skin tumors. We explored specific functions of cathepsin D during epidermal differentiation. Protein expression and enzymatic activity of cathepsin D increased in differentiated keratinocytes in both stratified organotypic cultures and in mouse skin during epidermal barrier repair. Treatment of cultured keratinocytes with exogenous cathepsin D increased the activity of transglutaminase 1, known to cross-link the cornified envelope proteins involucrin and loricrin during epidermal differentiation. Inhibition of cathepsin D by pepstatin A suppressed the activity of transglutaminase 1. Cathepsin D-deficient mice revealed reduced transglutaminase 1 activity and reduced protein levels of the cornified envelope proteins involucrin and loricrin. Also, amount and distribution of cornified envelope proteins involucrin, loricrin, filaggrin, and of the keratins K1 and K5 were significantly altered in cathepsin D-deficient mice. Stratum corneum morphology in cathepsin D-deficient mice was impaired, with increased numbers of corneocyte layers and faint staining of the cornified envelope only, which is similar to the human skin disease lamellar ichthyosis. Our findings suggest a functional link between cathepsin D activation, transglutaminase 1 activity and protein expression of cornified envelope proteins during epidermal differentiation.
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cathepsin d links tnf induced acid sphingomyelinase to bid mediated caspase 9 and 3 activation
Cell Death & Differentiation, 2004Co-Authors: Michael Heinrich, Marc Wickel, Wulf Schneiderbrachert, Supandi Winotomorbach, J Neumeyer, Marten Jakob, C Hallas, Vladimir Tchikov, Anna Trauzold, A HethkeAbstract:Acidic noncaspase Proteases-like cathepsins have been introduced as novel mediators of apoptosis. A clear role for these Proteases and the acidic endolysosomal compartment in apoptotic signalling is not yet defined. To understand the role and significance of noncaspases in promoting and mediating cell death, it is important to determine whether an intersection of these Proteases and the caspase pathway exists. We recently identified the endolysosomal Aspartate Protease cathepsin D (CTSD) as a target for the proapoptotic lipid ceramide. Here, we show that tumor necrosis factor (TNF)-induced CTSD activation depends on functional acid sphingomyelinase (A-SMase) expression. Ectopic expression of CTSD in CTSD-deficient fibroblasts results in an enhanced TNF-mediated apoptotic response. Intracellular colocalization of CTSD with the proapoptotic bcl-2 protein family member Bid in HeLa cells, and the ability of CTSD to cleave directly Bid in vitro as well as the lack of Bid activation in cathepsin-deficient fibroblasts indicate that Bid represents a direct downstream target of CTSD. Costaining of CTSD and Bid with Rab5 suggests that the endosomal compartments are the common 'meeting point'. Caspase-9 and -3 activation also was in part dependent on A-SMase and CTSD expression as revealed in the respective deficiency models. Our results link as novel endosomal intermediates the A-SMase and the acid Aspartate Protease CTSD to the mitochondrial apoptotic TNF pathway.
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cathepsin d targeted by acid sphingomyelinase derived ceramide
The EMBO Journal, 1999Co-Authors: Michael Heinrich, Marc Wickel, Wulf Schneiderbrachert, Christiane Sandberg, Julie Gahr, Josef Brunner, Ralf Schwandner, Thomas Weber, Martin KrönkeAbstract:Ceramide has been recognized as a common intracellular second messenger for various cytokines, growth factors and other stimuli, such as CD95, chemotherapeutic drugs and stress factors. To understand the role of ceramide during apoptosis and other cellular responses, it is critically important to characterize direct targets of ceramide action. In this paper, we show that ceramide specifically binds to and activates the endosomal acidic Aspartate Protease cathepsin D. Direct interaction of ceramide with cathepsin D results in autocatalytic proteolysis of the 52 kDa pre-pro cathepsin D to form the enzymatically active 48/32 kDa isoforms of cathepsin D. Acid sphingomyelinase (A-SMase)-deficient cells show decreased cathepsin D activity, which could be reconstituted by transfection with A-SMase cDNA. The results of our study identify cathepsin D as the first endosomal ceramide target that colocalizes with and may mediate downstream signaling effects of A-SMase.
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Cathepsin D targeted by acid sphingomyelinase‐derived ceramide
The EMBO Journal, 1999Co-Authors: Michael Heinrich, Marc Wickel, Christiane Sandberg, Julie Gahr, Josef Brunner, Wulf Schneider-brachert, Ralf Schwandner, Martin Krönke, Thomas Weber, Stefan SchützeAbstract:Ceramide has been recognized as a common intracellular second messenger for various cytokines, growth factors and other stimuli, such as CD95, chemotherapeutic drugs and stress factors. To understand the role of ceramide during apoptosis and other cellular responses, it is critically important to characterize direct targets of ceramide action. In this paper, we show that ceramide specifically binds to and activates the endosomal acidic Aspartate Protease cathepsin D. Direct interaction of ceramide with cathepsin D results in autocatalytic proteolysis of the 52 kDa pre-pro cathepsin D to form the enzymatically active 48/32 kDa isoforms of cathepsin D. Acid sphingomyelinase (A-SMase)-deficient cells show decreased cathepsin D activity, which could be reconstituted by transfection with A-SMase cDNA. The results of our study identify cathepsin D as the first endosomal ceramide target that colocalizes with and may mediate downstream signaling effects of A-SMase.
S. Sarrazin - One of the best experts on this subject based on the ideXlab platform.
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Caspase cleavage of the transcription factor FLI-1 during preB leukemic cell death.
BBA - Biochimica et Biophysica Acta, 2002Co-Authors: S. Sarrazin, Christelle Bonod-bidaud, P. Remy, P. Mehlen, F. MorleAbstract:Programmed cell death (apoptosis) is a complex phenomenon that is mediated in mammals mainly via the selective cleavage of intracellular proteins by the large family of cysteine Aspartate Protease caspases. Apoptosis is tightly regulated by the competitive effect of numerous proteins displaying either pro-apoptotic or anti-apoptotic activity. The ETS-family transcription factor FLI-1, frequently associated with malignant transformation, has been shown to display anti-apoptotic activity in several cell types including avian erythroblasts, mouse fibroblasts or lymphoid cells. We show here that apoptosis of murine preB leukemic cells is accompanied with the specific cleavage of FLI-1 by a caspase-like activity. We also demonstrate that the two isoforms of FLI-1 are indeed cleaved at three conserved sites by caspase 3 in vitro. The conservation of these cleavage sites among species suggests that the caspase cleavage of the anti-apoptotic transcription factor FLI-1 may represent a critical step to ensure irreversible cell death.Programmed cell death (apoptosis) is a complex phenomenon that is mediated in mammals mainly via the selective cleavage of intracellular proteins by the large family of cysteine Aspartate Protease caspases. Apoptosis is tightly regulated by the competitive effect of numerous proteins displaying either pro-apoptotic or anti-apoptotic activity. The ETS-family transcription factor FLI-1, frequently associated with malignant transformation, has been shown to display anti-apoptotic activity in several cell types including avian erythroblasts, mouse fibroblasts or lymphoid cells. We show here that apoptosis of murine preB leukemic cells is accompanied with the specific cleavage of FLI-1 by a caspase-like activity. We also demonstrate that the two isoforms of FLI-1 are indeed cleaved at three conserved sites by caspase 3 in vitro. The conservation of these cleavage sites among species suggests that the caspase cleavage of the anti-apoptotic transcription factor FLI-1 may represent a critical step to ensure irreversible cell death.
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Caspase cleavage of the transcription factor FLI-1 during preB leukemic cell death.
Biochimica et Biophysica Acta - Molecular Cell Research, 2002Co-Authors: S. Sarrazin, Christelle Bonod-bidaud, P. Remy, P. Mehlen, F. MorleAbstract:Programmed cell death (apoptosis) is a complex phenomenon that is mediated in mammals mainly via the selective cleavage of intracellular proteins by the large family of cysteine Aspartate Protease caspases. Apoptosis is tightly regulated by the competitive effect of numerous proteins displaying either pro-apoptotic or anti-apoptotic activity. The ETS-family transcription factor FLI-1, frequently associated with malignant transformation, has been shown to display anti-apoptotic activity in several cell types including avian erythroblasts, mouse fibroblasts or lymphoid cells. We show here that apoptosis of murine preB leukemic cells is accompanied with the specific cleavage of FLI-1 by a caspase-like activity. We also demonstrate that the two isoforms of FLI-1 are indeed cleaved at three conserved sites by caspase 3 in vitro. The conservation of these cleavage sites among species suggests that the caspase cleavage of the anti-apoptotic transcription factor FLI-1 may represent a critical step to ensure irreversible cell death.
