DOCSLIB.ORG

Caspase Activation & Apoptosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Caspase Activation & Apoptosis RnDSy-lu-2945 Caspase Activation & Apoptosis Extrinsic & Intrinsic Pathways of Caspase Activation CASPASE CLEAVAGE & ACTIVATION Caspases are a family of aspartate-specific, cysteine proteases that serve as the primary mediators of Pro-Domain Large Subunit (p20) Small Subunit (p10) apoptosis. Mammalian caspases can be subdivided into three functional groups, apoptotic initiator TRAIL Pro-Domain α chain β chain caspases (Caspase-2, -8, -9, -10), apoptotic effector caspases (Caspase-3, -6, -7), and caspases involved Asp-x Asp-x Proteolytic cleavage in inflammatory cytokine processing (Caspase-1, -4, -5, 11, and -12L/12S). All caspases are synthesized α chain as inactive zymogens containing a variable length pro-domain, followed by a large (20 kDa) and a small Fas Ligand TRAIL R1 Pro-Domain β chain TRAIL R2 Heterotetramer Formation (10 kDa) subunit. FADD FADD α chain α chain Pro-caspase-8, -10 Active caspase Pro-caspase-8, -10 TWEAK β chain Apoptotic caspases are activated upon the receipt of either an extrinsic or an intrinsic death signal. The Fas/CD95 extrinsic pathway (green arrows) is initiated by ligand binding to cell surface death receptors (TNF RI, Fas/ MAMMALIAN CASPASE DOMAINS & CLEAVAGE SITES FADD FADD TNF-α APOPTOTIC CASPASES CD95, DR3, TRAIL R1/DR4, TRAIL R2/DR5) followed by receptor oligomerization and cleavage of Pro- Extrinsic Pathway DR3 (or another TWEAK R) INITIATOR CASPASES 152 316 331 Pro-caspase-8, -10 Pro-caspase-8, -10 1 435 caspase-8 and -10. Activation of Caspase-8 and Caspase-10 results in the cleavage of BID and Caspase-2 CARD TRADD FLIP TRADD downstream effector caspases. The intrinsic pathway of caspase activation (purple arrows) is initiated by TNF RI ARC 216 374 385 FADD TRAF-2 1 479 Caspase-8, -10 Caspase-8 DED DED RIP1 events such as DNA damage, growth factor withdrawal, or loss of contact with the extracellular matrix. TRADD BID Pro-caspase-8, -10 DD RIP1 TRADD DED 138 315 331 tBID 1 416 These events lead to changes in the integrity of the mitochondrial membrane that result in the release of TRAF-2 Caspase-9 CARD Pro-caspase-8, -10 BAK Cytochrome c pro-apoptotic proteins including Cytochrome c, Smac/Diablo, HTRA2/Omi, Apoptosis-Inducing Factor (AIF), Death Domain (DD) 219 415 SMAC/Diablo 1 521 Death Effector Domain (DED) Caspase-9 IAPs Caspase-10 DED DED and Endonuclease G. tBID HTRA2/Omi IAPs tBID tBID tBID 14-3-3 Bad Bad BAK BAK Bcl-2 Bax 28 175 P P EFFECTOR CASPASES 1 277 P Caspase-3 Mitochondrial membrane permeability is regulated by the Bcl-2 family of proteins. The balance between Bad Bcl-2 Bcl-xL Pro-caspase-3 23 179 194 Caspase Recruitment 1 293 BAK Bcl-xL Caspase-3 pro- and anti-apoptotic family members determines whether or not a cell will undergo apoptosis. In healthy Domain (CARD) Target Molecules Caspase-6 APAF-1 (e.g. Actin, 23 198 tBID Pro-caspase-9 Nuclear lamins, 1 303 cells, Bcl-2 and Bcl-xL inhibit apoptosis by binding to the pro-apoptotic Bax and BAK proteins. Bad is also Bax Pro-caspase-7 Bad Bcl-xL Apoptosome ICAD, PARP) Caspase-7 BAK Caspase-7 BAK tBID Cytochrome c phosphorylated and sequestered in the cytoplasm by the 14-3-3 protein in these cells. If cytoplasmic levels tBID Bcl-2 INFLAMMATORY CASPASES Bcl-xL 119 297 317 Bax 1 404 Bcl-x tBID of free BAD increase, Bcl-2 and Bcl-xL bind to Bad and release Bax and BAK. Bax and BAK, or processed L Bcl-2 Bcl-2 Caspase-1 CARD Cytochrome c Bad tBID Pro-caspase-6 Bax Bax Caspase-6 93 270 290 forms of these proteins, can then insert into the mitochondrial membrane, compromising its integrity. Bad Cytochrome c Cytochrome c 1 377 tBID Caspase-4 CARD Bax AIF HSPs 134 311 331 Bad 1 418 Bax BID Caspase-5 CARD Initiator caspases are activated in three distinct protein complexes, the death-inducing signaling complex Endo G 1 373 (DISC; Caspase-8 and -10), the apoptosome (Caspase-9), and the PIDDosome (Caspase-2). The DISC is 14-3-3 ARC Caspase-2 Caspase-11 CARD P P 1 125 formed following ligand binding and death receptor oligomerization. Pro-caspase-8 and Pro-caspase-10 P PIDDosome Caspase-12S CARD Bad DNA FRAGMENTATION 1 419 Caspase-12L CARD are recruited to the death receptors through their interactions with the adaptor protein, FADD. This Pro-caspase-2 CASPASE ACTIVATING COMPLEXES interaction is mediated by their shared death effector domains (DED). Clustering of pro-caspases near the CRADD/RAIDD DISC INTERACTING DOMAINS INHIBITORS OF COMPLEX FORMATION death receptors results in their cleavage and activation. In contrast, Pro-caspase-9 is activated following CARD Fas Ligand DD DNA DAMAGE an intrinsic change associated with the release of Cytochrome c from the mitochondria. In the cytoplasm, x x x Fas/CD95 DD PIDD x DD x FADD DD/DED Cytochrome c interacts with APAF-1, which recruits Pro-caspase-9 by way of its caspase recruitment P Pro-apoptotic: Anti-apoptotic: p53 p53 p53 • Bad • PUMA • 14-3-3 Pro-caspase-8,-10 DED domain (CARD) to form the apoptosome. Formation of the apoptosome leads to the cleavage and • Bax • PIDD • p21 DED DD • BID others others FLIP ARC activation of Caspase-9. Intrinsic cellular changes can also lead to the activation of Caspase-2. Following • Noxa APOPTOSOME INTERACTING DOMAINS INHIBITORS OF COMPLEX FORMATION DNA damage, p53 induces the expression of p53-induced protein with a death domain (PIDD), which Intrinsic Pathway HSP27 Cytochrome c HSP70 HSP27 associates with the CRADD/RAIDD adaptor protein and Pro-caspase-2 to form the PIDDosome. The Cytochrome c APAF-1 CARD association between CRADD/RAIDD and PIDD is mediated by their shared death domains (DD), while Pro-caspase-9 CARD APAF-1 NUCLEUS CARD domains mediate the interaction between CRADD/RAIDD and Pro-caspase-2. Formation of the PIDDOSOME INTERACTING DOMAINS PIDD DD PIDDosome leads to the cleavage of Pro-caspase-2. CRADD/RAIDD DD/CARD Pro-caspase-2 CARD Autocatalytic cleavage of the initiator pro-caspases occurs at aspartic acid residues located after the pro- INFLAMMASOME INTERACTING DOMAINS domain, and in between the large and the small subunits. Upon cleavage, mature caspases form a NALP3, NALP1 or IPAF Pyrin DOMAIN KEY proteolytically active heterotetramer consisting of two small and two large subunits. Once activated, Death Domain (DD) ASC Pyrin/CARD Death Effector Domain (DED) initiator caspases cleave downstream effector caspases that promote the ordered disassembly of the cell Caspase Recruitment Pro-caspase-1 CARD Domain (CARD) by targeting a number of critical cellular proteins including structural proteins, DNA repair proteins, and Pyrin Domain proteins involved in signal transduction pathways. NOTE: This poster conveys a general overview and should be considered neither comprehensive nor definitive. The details of this information are understood to be subject to interpretation. © R&D Systems 2016 Learn more | rndsystems.com/apoptosis Global [email protected] [email protected] North America TEL 800 343 7475 Europe | Middle East | Africa TEL +44 (0)1235 529449 China [email protected] TEL +86 (21) 52380373 Rest of World bio-techne.com/find-us/distributors TEL +1 612 379 2956 Rnlu Wall Poster RnDSy-lu-2945 Caspase Activation & Apoptosis Extrinsic & Intrinsic Pathways of Caspase Activation CASPASE CLEAVAGE & ACTIVATION Caspases are a family of aspartate-specific, cysteine proteases that serve as the primary mediators of Pro-Domain Large Subunit (p20) Small Subunit (p10) apoptosis. Mammalian caspases can be subdivided into three functional groups, apoptotic initiator TRAIL Pro-Domain α chain β chain caspases (Caspase-2, -8, -9, -10), apoptotic effector caspases (Caspase-3, -6, -7), and caspases involved Asp-x Asp-x Proteolytic cleavage in inflammatory cytokine processing (Caspase-1, -4, -5, 11, and -12L/12S). All caspases are synthesized α chain as inactive zymogens containing a variable length pro-domain, followed by a large (20 kDa) and a small Fas Ligand TRAIL R1 Pro-Domain β chain TRAIL R2 Heterotetramer Formation (10 kDa) subunit. FADD FADD α chain α chain Pro-caspase-8, -10 Active caspase Pro-caspase-8, -10 TWEAK β chain Apoptotic caspases are activated upon the receipt of either an extrinsic or an intrinsic death signal. The Fas/CD95 extrinsic pathway (green arrows) is initiated by ligand binding to cell surface death receptors (TNF RI, Fas/ MAMMALIAN CASPASE DOMAINS & CLEAVAGE SITES FADD FADD TNF-α APOPTOTIC CASPASES CD95, DR3, TRAIL R1/DR4, TRAIL R2/DR5) followed by receptor oligomerization and cleavage of Pro- Extrinsic Pathway DR3 (or another TWEAK R) INITIATOR CASPASES 152 316 331 Pro-caspase-8, -10 Pro-caspase-8, -10 1 435 caspase-8 and -10. Activation of Caspase-8 and Caspase-10 results in the cleavage of BID and Caspase-2 CARD TRADD FLIP TRADD downstream effector caspases. The intrinsic pathway of caspase activation (purple arrows) is initiated by TNF RI ARC 216 374 385 FADD TRAF-2 1 479 Caspase-8, -10 Caspase-8 DED DED RIP1 events such as DNA damage, growth factor withdrawal, or loss of contact with the extracellular matrix. TRADD BID Pro-caspase-8, -10 DD RIP1 TRADD DED 138 315 331 tBID 1 416 These events lead to changes in the integrity of the mitochondrial membrane that result in the release of TRAF-2 Caspase-9 CARD Pro-caspase-8, -10 BAK Cytochrome c pro-apoptotic proteins including Cytochrome c, Smac/Diablo, HTRA2/Omi, Apoptosis-Inducing Factor (AIF), Death Domain (DD) 219 415 SMAC/Diablo 1 521 Death Effector Domain (DED) Caspase-9 IAPs Caspase-10 DED DED and Endonuclease G. tBID HTRA2/Omi IAPs tBID tBID tBID 14-3-3 Bad Bad BAK BAK Bcl-2 Bax 28 175 P P EFFECTOR CASPASES 1 277 P Caspase-3 Mitochondrial membrane permeability is regulated by the Bcl-2 family of proteins.
Load more

Recommended publications
  • Accumulation of P53 and Reductions in XIAP Abundance Promote the Apoptosis of Prostate Cancer Cells
    Research Article Accumulation of p53 and Reductions in XIAP Abundance Promote the Apoptosis of Prostate Cancer Cells Subhra Mohapatra, Baoky Chu, Xiuhua Zhao, and W.J. Pledger Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute and the University of South Florida Medical Center, Tampa, Florida Abstract activates caspase-9. Most drugs signal apoptosis through the Toward the goal of developing effective treatments for mitochondrial pathway. prostate cancers, we examined the effects of cyclin-dependent Proteins that modulate caspase activity and thus determine kinase inhibitors on the survival of prostate cancer cells. We whether cells live or die include the inhibitor of apoptosis proteins show that roscovitine, R-roscovitine, and CGP74514A (collec- (IAPs) and the Bcl-2 proteins. The IAP family includes cIAP-1, cIAP- tively referred to as CKIs) induce the apoptosis of LNCaP and 2, XIAP, and survivin (11). Of these proteins, XIAP is the most potent. LNCaP-Rf cells, both of which express wild-type p53. Apoptosis IAPs interact with and inhibit the activity of processed caspases; required caspase-9 and caspase-3 activity, and cytochrome c thus, they function as ‘‘brakes’’ that can impede the apoptotic accumulated in the cytosol of CKI-treated cells. Amounts of process once it begins. IAPs inactivate both initiator and effector caspases; caspase-9 and caspase-3 are IAP targets, whereas caspase- p53 increased substantially in CKI-treated cells, whereas amounts of the endogenous caspase inhibitor XIAP decreased. 8 is not (12). CKIs did not appreciably induce the apoptosis of LNCaP cells The Bcl-2 proteins are critical determinants of mitochondria- treated with pifithrin-A, which prevents p53 accumulation, or dependent caspase activation (13).
    [Show full text]
  • Manner Via Caspase-8 in an RIP3
    Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1 β and IL-18 Maturation via Caspase-8 in an RIP3-Independent Manner This information is current as of October 2, 2021. Lukas Bossaller, Ping-I Chiang, Christian Schmidt-Lauber, Sandhya Ganesan, William J. Kaiser, Vijay A. K. Rathinam, Edward S. Mocarski, Deepa Subramanian, Douglas R. Green, Neal Silverman, Katherine A. Fitzgerald, Ann Marshak-Rothstein and Eicke Latz Downloaded from J Immunol 2012; 189:5508-5512; Prepublished online 9 November 2012; doi: 10.4049/jimmunol.1202121 http://www.jimmunol.org/content/189/12/5508 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/11/12/jimmunol.120212 Material 1.DC1 References This article cites 30 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/189/12/5508.full#ref-list-1 by guest on October 2, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved.
    [Show full text]
  • The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies
    Hindawi Publishing Corporation International Journal of Cell Biology Volume 2010, Article ID 215158, 21 pages doi:10.1155/2010/215158 Review Article TheRoleofCyclooxygenase-2inCellProliferationandCell Death in Human Malignancies Cyril Sobolewski,1 Claudia Cerella,1 Mario Dicato,1 Lina Ghibelli,2 and Marc Diederich1 1 LaboratoiredeBiologieMol´eculaire et Cellulaire du Cancer, Hopitalˆ Kirchberg, 9 rue Edward Steichen, 2540 Luxembourg, Luxembourg 2 Dipartimento di Biologia, Universita` di Roma di Roma Tor Vergata, Via Ricerca Scientifica snc, 00133 Rome, Italy Correspondence should be addressed to Marc Diederich, [email protected] Received 16 July 2009; Accepted 18 December 2009 Academic Editor: Simone Fulda Copyright © 2010 Cyril Sobolewski et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It is well admitted that the link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways, which act during the different steps of tumorigenesis. The cyclooxygenases (COXs) are a family of enzymes, which catalyze the rate-limiting step of prostaglandin biosynthesis. This family contains three members: ubiquitously expressed COX- 1, which is involved in homeostasis; the inducible COX-2 isoform, which is upregulated during both inflammation and cancer; and COX-3, expressed in brain and spinal cord, whose functions remain to be elucidated. COX-2 was described to modulate cell proliferation and apoptosis mainly in solid tumors, that is, colorectal, breast, and prostate cancers, and, more recently, in hematological malignancies. These findings prompt us to analyze here the effects of a combination of COX-2 inhibitors together with different clinically used therapeutic strategies in order to further improve the efficiency of future anticancer treatments.
    [Show full text]
  • Biochemical Society Focused Meetings Proteases A
    ORE Open Research Exeter TITLE Proteases and caspase-like activity in the yeast Saccharomyces cerevisiae. AUTHORS Wilkinson, D; Ramsdale, M JOURNAL Biochemical Society Transactions DEPOSITED IN ORE 18 November 2013 This version available at http://hdl.handle.net/10871/13957 COPYRIGHT AND REUSE Open Research Exeter makes this work available in accordance with publisher policies. A NOTE ON VERSIONS The version presented here may differ from the published version. If citing, you are advised to consult the published version for pagination, volume/issue and date of publication Biochemical Society Transactions (2011) XX, (XX-XX) (Printed in Great Britain) Biochemical Society Focused Meetings Proteases and caspase-like activity in the yeast Saccharomyces cerevisiae Derek Wilkinson and Mark Ramsdale1 Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, EX4 4QD Key words: Programmed cell death, apoptosis, necrosis, proteases, caspases, Saccharomyces cerevisiae. Abbreviations used: PCD, programmed cell death; ROS, reactive oxygen species; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ER, endoplasmic reticulum; MS, mass spectrometry. 1email [email protected] Abstract A variety of proteases have been implicated in yeast PCD including the metacaspase, Mca1 and the separase Esp1, the HtrA-like serine protease Nma111, the cathepsin-like serine carboxypeptideases and a range of vacuolar proteases. Proteasomal activity is also shown to have an important role in determining cell fate, with both pro- and anti-apoptotic roles. Caspase-3, -6- and -8 like activities are detected upon stimulation of yeast PCD, but not all of this activity is associated with Mca1, implicating other proteases with caspase-like activity in the yeast cell death response.
    [Show full text]
  • Life, Death, and the Pursuit of Apoptosis
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Life, death, and the pursuit of apoptosis Eileen White Center for Advanced Biotechnology and Medicine and Department of Biological Sciences and the Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854 USA Apoptosis or programmed cell death is a genetically con- (Oltvai et al. 1993). Bcl-2 is expressed widely during em- trolled response for cells to commit suicide. The symp- bryogenesis (LeBrun et al. 1993; Novack and Korsmeyer toms of apoptosis are viability loss accompanied by cy- 1994), and its expression becomes more restricted in toplasmic boiling, chromatin condensation, and DNA adult tissues to those requiring long-term survival (stem fragmentation (Wyllie 1980). Pathologists and develop- cells, postmitotic neurons, and proliferating zones; mental biologists have cataloged the occurrences of ap- Hockenbery et al. 1991). optosis for many years based on these defined morpho- Apoptosis plays a major role in normal development, logical features, but what has propelled apoptosis into and it was expected that gain- or loss-of-function of a the forefront of basic research has been the identification death inhibitor such as Bcl-2 would have a phenotype in of genes that control cell death and the appreciation of transgenic mice. Bcl-2 was expected to regulate apopto- the role of apoptosis in development and disease. Regu- sis in lymphoid cells because of the role of Bcl-2 in hu- lation of cell death is essential for normal development man B cell lymphoma. Targeted Bcl-2 overexpression to and is an important defense against viral infection and the lymphoid system extends normal B cell survival the emergence of cancer.
    [Show full text]
  • Apoptotic Threshold Is Lowered by P53 Transactivation of Caspase-6
    Apoptotic threshold is lowered by p53 transactivation of caspase-6 Timothy K. MacLachlan*† and Wafik S. El-Deiry*‡§¶ʈ** *Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, and Departments of ‡Medicine, §Genetics, ¶Pharmacology, and ࿣Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 Communicated by Britton Chance, University of Pennsylvania School of Medicine, Philadelphia, PA, April 23, 2002 (received for review January 11, 2002) Little is known about how a cell’s apoptotic threshold is controlled Inhibition of the enzyme reduces the sensitivity conferred by after exposure to chemotherapy, although the p53 tumor suppres- overexpression of p53. These results identify a pathway by which sor has been implicated. We identified executioner caspase-6 as a p53 is able to accelerate the apoptosis cascade by loading the cell transcriptional target of p53. The mechanism involves DNA binding with cell death proteases so that when an apoptotic signal is by p53 to the third intron of the caspase-6 gene and transactiva- received, programmed cell death occurs rapidly. tion. A p53-dependent increase in procaspase-6 protein level al- lows for an increase in caspase-6 activity and caspase-6-specific Materials and Methods Lamin A cleavage in response to Adriamycin exposure. Specific Western Blotting and Antibodies. Immunoblotting was carried out by inhibition of caspase-6 blocks cell death in a manner that correlates using mouse anti-human p53 monoclonal (PAb1801; Oncogene), with caspase-6 mRNA induction by p53 and enhances long-term rabbit anti-human caspase-3 (Cell Signaling, Beverly, MA), mouse survival in response to a p53-mediated apoptotic signal.
    [Show full text]
  • Combination of the Natural Compound Periplocin and TRAIL Induce
    Han et al. Journal of Experimental & Clinical Cancer Research (2019) 38:501 https://doi.org/10.1186/s13046-019-1498-z RESEARCH Open Access Combination of the natural compound Periplocin and TRAIL induce esophageal squamous cell carcinoma apoptosis in vitro and in vivo: Implication in anticancer therapy Lujuan Han1†, Suli Dai1†, Zhirong Li1, Cong Zhang1, Sisi Wei1, Ruinian Zhao1, Hongtao Zhang2, Lianmei Zhao1* and Baoen Shan1* Abstract Background: Esophageal cancer is one of the most common malignant tumors in the world. With currently available therapies, only 20% ~ 30% patients can survive this disease for more than 5 years. TRAIL, a natural ligand for death receptors that can induce the apoptosis of cancer cells, has been explored as a therapeutic agent for cancers, but it has been reported that many cancer cells are resistant to TRAIL, limiting the potential clinical use of TRAIL as a cancer therapy. Meanwhile, Periplocin (CPP), a natural compound from dry root of Periploca sepium Bge, has been studied for its anti-cancer activity in a variety of cancers. It is not clear whether CPP and TRAIL can have activity on esophageal squamous cell carcinoma (ESCC) cells, or whether the combination of these two agents can have synergistic activity. Methods: We used MTS assay, flow cytometry and TUNEL assay to detect the effects of CPP alone or in combination with TRAIL on ESCC cells. The mechanism of CPP enhances the activity of TRAIL was analyzed by western blot, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay. The anti-tumor effects and the potential toxic side effects of CPP alone or in combination with TRAIL were also evaluated in vivo.
    [Show full text]
  • Structural and Functional Diversity of Caspase Homologues in Non-Metazoan Organisms
    Protoplasma DOI 10.1007/s00709-017-1145-5 REVIEW ARTICLE Structural and functional diversity of caspase homologues in non-metazoan organisms Marina Klemenčič1,2 & Christiane Funk1 Received: 1 June 2017 /Accepted: 5 July 2017 # The Author(s) 2017. This article is an open access publication Abstract Caspases, the proteases involved in initiation and supports the role of metacaspases and orthocaspases as im- execution of metazoan programmed cell death, are only pres- portant contributors to cell homeostasis during normal physi- ent in animals, while their structural homologues can be ological conditions or cell differentiation and ageing. found in all domains of life, spanning from simple prokary- otes (orthocaspases) to yeast and plants (metacaspases). All members of this wide protease family contain the p20 do- Keywords Algae . Cyanobacteria . Cell death . Cysteine main, which harbours the catalytic dyad formed by the two protease . Metacaspase . Orthocaspase amino acid residues, histidine and cysteine. Despite the high structural similarity of the p20 domain, metacaspases and orthocaspases were found to exhibit different substrate speci- ficities than caspases. While the former cleave their substrates Introduction after basic amino acid residues, the latter accommodate sub- strates with negative charge. This observation is crucial for BOut of life’s school of war: What does not destroy me, the re-evaluation of non-metazoan caspase homologues being makes me stronger.^ wrote the German philosopher involved in processes of programmed cell death. In this re- Friedrich Nietzsche in his book Twilight of the Idols or view, we analyse the structural diversity of enzymes contain- how to philosophize with a hammer. Even though ing the p20 domain, with focus on the orthocaspases, and reformatted to more common use, this phrase has been summarise recent advances in research of orthocaspases and used to describe the dual nature of caspase homologues metacaspases of cyanobacteria, algae and higher plants.
    [Show full text]
  • XIAP's Profile in Human Cancer
    biomolecules Review XIAP’s Profile in Human Cancer Huailu Tu and Max Costa * Department of Environmental Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA; [email protected] * Correspondence: [email protected] Received: 16 September 2020; Accepted: 25 October 2020; Published: 29 October 2020 Abstract: XIAP, the X-linked inhibitor of apoptosis protein, regulates cell death signaling pathways through binding and inhibiting caspases. Mounting experimental research associated with XIAP has shown it to be a master regulator of cell death not only in apoptosis, but also in autophagy and necroptosis. As a vital decider on cell survival, XIAP is involved in the regulation of cancer initiation, promotion and progression. XIAP up-regulation occurs in many human diseases, resulting in a series of undesired effects such as raising the cellular tolerance to genetic lesions, inflammation and cytotoxicity. Hence, anti-tumor drugs targeting XIAP have become an important focus for cancer therapy research. RNA–XIAP interaction is a focus, which has enriched the general profile of XIAP regulation in human cancer. In this review, the basic functions of XIAP, its regulatory role in cancer, anti-XIAP drugs and recent findings about RNA–XIAP interactions are discussed. Keywords: XIAP; apoptosis; cancer; therapeutics; non-coding RNA 1. Introduction X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3), baculoviral IAP repeat-containing protein 4 (BIRC4), and human IAPs like protein (hILP), belongs to IAP family which was discovered in insect baculovirus [1]. Eight different IAPs have been isolated from human tissues: NAIP (BIRC1), BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4), BIRC5 (survivin), BIRC6 (apollon), BIRC7 (livin) and BIRC8 [2].
    [Show full text]
  • Calpain Inhibitors Prevent Nitric Oxide-Triggered Excitotoxic Apoptosis
    Calpain inhibitors prevent nitric oxide- triggered excitotoxic apoptosis Christiane Volbracht,1,2 Eugenio Fava,1,3 Marcel Leist1,4 and Pierluigi Nicotera1,3,CA 1Molecular Toxicology, University of Konstanz, Konstanz, Germany; 2Institute of Molecular and Cell Biology, Singapore 117609, Singapore; 3MRC Toxicology Unit, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN; 4Department of Neurobiology, H. Lundbeck A/S, 2500 Valby, Denmark CACorresponding Author The pathogenesis of some neurodegenerative disorders has potential, chromatin breakdown, and subsequent death of been linked to excitotoxicity, excess generation of nitric oxide cerebellar granule neurons exposed to NO donors (S-nitroso- (NO) and apoptosis. Here, we used a model of NO-triggered L-glutathione, S-nitroso-N-acetyl-D,L-penicillamine, and diethy- neuronal apoptosis that was strictly dependent on autocrine lamino-diazenolate-2-oxide). Since inhibitors did not interfere 2 NMDA receptor (NMDA-R) activation and intracellular Ca with NMDA-R activation, we suggest that block of calpains increase. We investigated the ef®ciency and potentially bene- blunts NO-triggered neuronal apoptosis by stopping the ®cial effects of calpain inhibition. Three calpain inhibitors that cascade downstream of primary autocrine excitotoxic events. prevented intracellular fodrin proteolysis also blocked apopto- NeuroReport 12:3645±3648 & 2001 Lippincott Williams & tic features such as decrease in mitochondrial membrane Wilkins. Key words: Apoptosis; Calpains; Excitotoxicity; Mitochondria; Nitric oxide INTRODUCTION MATERIALS AND METHODS Massive generation of the pleiotropic messenger molecule Cell culture: Murine CGC were isolated from 8-day-old nitric oxide (NO) has been implicated in many neuro- speci®c pathogen free BALB/e mice obtained from the pathological conditions including ischemia [1].
    [Show full text]
  • Production of Circularly Permuted Caspase-2 for Affinity Fusion-Tag
    biomolecules Article Production of Circularly Permuted Caspase-2 for Affinity Fusion-Tag Removal: Cloning, Expression in Escherichia coli, Purification, and Characterization 1,2, 1,2, , 1,3 1,3 Monika Cserjan-Puschmann y , Nico Lingg * y , Petra Engele , Christina Kröß , Julian Loibl 1, Andreas Fischer 1, Florian Bacher 1, Anna-Carina Frank 1,2, Christoph Öhlknecht 1,4,Cécile Brocard 5, Chris Oostenbrink 1,4 , Matthias Berkemeyer 5, Rainer Schneider 1,3, Gerald Striedner 1,2 and Alois Jungbauer 1,2,* 1 ACIB-Austrian Centre of Industrial Biotechnology, Muthgasse 18, 1190 Vienna, Austria; [email protected] (M.C.-P.); [email protected] (P.E.); [email protected] (C.K.); [email protected] (J.L.); andreas.fi[email protected] (A.F.); fl[email protected] (F.B.); [email protected] (A.-C.F.); [email protected] (C.Ö.); [email protected] (C.O.); [email protected] (R.S.); [email protected] (G.S.) 2 Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria 3 Institute of Biochemistry, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria 4 Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria 5 Biopharma Process Science Austria, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria; [email protected] (C.B.); [email protected] (M.B.) * Correspondence: [email protected] (N.L.); [email protected] (A.J.) These authors have contributed equally to the manuscript.
    [Show full text]
  • Serine Proteases with Altered Sensitivity to Activity-Modulating
    (19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants.
    [Show full text]