DOCSLIB.ORG

Regulation of Cancer Metastasis by TRAIL/Death Receptor Signaling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulation of Cancer Metastasis by TRAIL/Death Receptor Signaling biomolecules Review Regulation of Cancer Metastasis by TRAIL/Death Receptor Signaling You-Take Oh and Shi-Yong Sun * Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-404-778-2170 Abstract: Death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; TNFSF10) and their corresponding death receptors (e.g., DR5) not only initiate apoptosis through activation of the extrinsic apoptotic pathway but also exert non-apoptotic biological functions such as regulation of inflammation and cancer metastasis. The involvement of the TRAIL/death receptor signaling pathway in the regulation of cancer invasion and metastasis is complex as both positive and negative roles have been reported. The underlying molecular mechanisms are even more complicated. This review will focus on discussing current knowledge in our understanding of the involvement of TRAIL/death receptor-mediated signaling in the regulation of cancer cell invasion and metastasis. Keywords: TRAIL; death receptor; apoptosis; invasion; metastasis; cancer 1. Introduction Metastasis is a key cause of cancer death. To metastasize to distant organ sites, cancer cells must detach from the primary tumor sites (local invasion; intravasation), Citation: Oh, Y.-T.; Sun, S.-Y. translocate into the circulatory system, survive in the circulation and arrest at a distant Regulation of Cancer Metastasis by organ site (extravasation), and finally adapt to the new microenvironment of distant tissues TRAIL/Death Receptor Signaling. (micrometastasis formation; metastatic colonization) [1]. Therefore, cell death is a key Biomolecules 2021, 11, 499. https:// mechanism for preventing the dissemination of metastatic cells. Cell death can occur after doi.org/10.3390/biom11040499 the detachment of primary tumor cells from the extracellular matrix, in the circulation through tumor immune surveillance or destruction by mechanical stresses, and after Academic Editor: Ladislav Andˇera extravasation during the phase of micrometastasis formation in a secondary organ [2]. It has been estimated that only about <0.01% of cancer cells that enter the circulation are able Received: 4 February 2021 to eventually survive and develop lung metastasis [3,4]. This makes metastasis a highly Accepted: 24 March 2021 Published: 26 March 2021 inefficient process: very few of the cancer cells that migrate from the primary tumor can successfully colonize in distant sites [1]. Apoptosis represents a major form of cell death. Thus, the acquisition of apoptosis Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in resistance is a key hallmark of cancer and occurs early during tumorigenesis [5]. Ac- published maps and institutional affil- cordingly, it seems logical that the selection of cancer cells with greater deregulation of iations. apoptosis will be necessary for strong metastasis. It is well known that the extrinsic death receptor-mediated apoptotic pathway plays a critical role in host immune surveillance against cancer [6–8]. However, an increasing body of research suggests that this death signaling pathway also exerts non-apoptotic functions in enhancing cancer growth or metastasis. This review will primarily focus on discussing current knowledge in our under- Copyright: © 2021 by the authors. standing of the involvement of the extrinsic apoptotic pathway, particularly tumor necrosis Licensee MDPI, Basel, Switzerland. This article is an open access article factor-related apoptosis-inducing ligand (TRAIL)/death receptor-mediated signaling, in distributed under the terms and the regulation of cancer cell metastasis. conditions of the Creative Commons 2. TRAIL/Death Receptor-Mediated Apoptotic Signaling Pathway Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ There are two TRAIL death receptors in humans: death receptor 5 (DR5; also called 4.0/). TRAIL-R2, TNFRSF10B or Killer/DR5) and death receptor 4 (DR4; also called TRAIL-R1 Biomolecules 2021, 11, 499. https://doi.org/10.3390/biom11040499 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 16 Biomolecules 2021, 112., 499TRAIL/Death Receptor-Mediated Apoptotic Signaling Pathway 2 of 16 There are two TRAIL death receptors in humans: death receptor 5 (DR5; also called TRAIL-R2, TNFRSF10B or Killer/DR5) and death receptor 4 (DR4; also called TRAIL-R1 or TNFRSF10A).or TNFRSF10A).Both DR5 and BothDR4 DR5share and redu DR4ndant share functions redundant in triggering functions apoptosis in triggering apoptosis but have some butdistinct have biological some distinct functions, biological such as functions, regulation such of cancer as regulation cell metastasis, of cancer as cell metastasis, discussed below.as discussedIn contrast, below. there In is contrast, only one there TRAIL is only death one receptor TRAIL deathnamed receptor murine named murine TRAIL death receptorTRAIL death(mDR) receptor in mice (mDR)[9,10] or in mouse mice [9 homolog,10] or mouse of KILLER/DR5 homolog of (MK) KILLER/DR5 [11]. (MK) [11]. TRAIL ligationTRAIL to its functional ligation to cell its surface functional death cell receptors surface death or induction receptors of or death induction receptor of death receptor trimerization ortrimerization aggregation or(e.g., aggregation via overexpr (e.g.,ession via or overexpression agonistic antibodies) or agonistic leads antibodies)to re- leads to cruitment of therecruitment adaptor protein, of the adaptorFas-associ protein,ated death Fas-associated domain (FADD), death domain to the cytoplasmic (FADD), to the cytoplasmic region of the receptorregion of followed the receptor by recruitm followedent by of recruitment pro-caspase-8 of pro-caspase-8or pro-caspase-10. or pro-caspase-10. The The formation of thisformation death-inducing of this death-inducing signaling complex signaling (DISC) complex triggers (DISC) cleavage triggers and cleavage activa- and activation tion of caspase-8of or caspase-8 caspase-10, or caspase-10, which in turn which activates in turn downstream activates downstream caspase-3, caspase-3,-6, and -7, -6, and -7, and and eventual apoptosiseventual [12,13]. apoptosis Therefore, [12,13]. Therefore,TRAIL/death TRAIL/death receptor/FADD/caspase-8 receptor/FADD/caspase-8 signal- signaling ing normally triggersnormally apoptotic triggers cell apoptotic death (Figure cell death 1A). (Figure 1A). Figure 1. TumorFigure necrosis 1. Tumor factor-related necrosis factor-related apoptosis-inducing apoptosis-inducing ligand (TRAIL)/death ligand (TRAIL)/death receptor signalingreceptor signaling in the regulation of apoptosis andin the metastasis regulation of cancer of apoptosis cells. (A and) Under metastasis normal of apoptotic cancer cells. conditions (A) Under (e.g., normal in cancer apoptotic cells sensitive conditions to TRAIL with (e.g., in cancer cells sensitive to TRAIL with activated death receptor pathway), TRAIL ligation with activated death receptor pathway), TRAIL ligation with its death receptors (DR4 and DR5) or an agonistic antibody binding its death receptors (DR4 and DR5) or an agonistic antibody binding to a corresponding death recep- to a corresponding death receptor (DR4 or DR5) on the surface of cancer cells induces the formation of the death-inducing tor (DR4 or DR5) on the surface of cancer cells induces the formation of the death-inducing signaling signaling complexcomplex (DISC) (DISC) involving involving Fas-associated Fas-associated death death domain domain (FADD) (FADD) recruitment recruitment of pro-caspase-8 of pro-caspase-8 via its via death effector domain, resultingits death in effector caspase-8 domain, or -10 activationresulting in followed caspase-8 by or cleavage -10 activation and activation followed of by caspase-3, cleavage -6, and and activa- -7, and eventual execution oftion apoptosis of caspase-3, or anoikis. -6, and This -7, mechanismand eventual restricts execution the of formation apoptosis of or the anoikis. metastasis This and mechanism invasion restricts signaling complex (MISC) andthe subsequently formation of suppresses the metastasis cell invasion and invasion and metastasis. signaling Whencomple TRAIL/deathx (MISC) and receptors subsequently are inhibited sup- or their functions arepresses compromised, cell invasion available and FADDmetastasis. and caspase-8 When TRAIL/ may recruitdeath andreceptors stabilize are TNF-receptor-associatedinhibited or their functions factor (TRAF)2 with the helpare of compromised, S1P, resulting available in enhanced FADD TRAF2 and caspase-8 polyubiquitination may recruit and and activation, stabilize TNF-receptor-associated likely through a self-ubiquitination mechanism.factor This will(TRAF)2 further with lead the to help activation of S1P, of resulting ERK/JNK/AP-1 in enhanced signaling TRAF2 and polyubiquitination NF-κB activation, whichand activa- activates MMPs tion, likely through a self-ubiquitination mechanism. This will further lead to activation of (e.g., MMP1) and enhances the release of inflammatory cytokines (e.g., monocyte chemoattractant protein 1 (MCP1)) that ERK/JNK/AP-1 signaling and NF-κB activation, which activates MMPs (e.g., MMP1) and enhances promote invasion and metastasis of cancer cells. MCP1 may induce monocyte chemotactic protein-induced protein-1 the release of inflammatory cytokines (e.g., monocyte chemoattractant protein 1 (MCP1)) that pro- (MCPIP1) expression,mote invasion leading and metastasis
Load more

Recommended publications
  • 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]
  • Chemokine Receptor CXCR3 Promotes Colon Cancer Metastasis to Lymph Nodes
    Oncogene (2007) 26, 4679–4688 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes K Kawada1,2,5, H Hosogi1,2,5, M Sonoshita1, H Sakashita3, T Manabe3, Y Shimahara2, Y Sakai2, A Takabayashi4, M Oshima1 and MM Taketo1 1Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 3Department of Clinical Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan and 4Kitano Hospital Medical Institute, Osaka, Japan Chemokines and their receptors are essential for leuko- inflammatory cytokines, growth factors and/or patho- cyte trafficking, and also implicated in cancer metastasis genic stimuli. Important roles of chemokines and their to specific organs. We have recently demonstrated that receptors have been demonstrated in inflammation, CXCR3 plays a critical role in metastasis of mouse infection, tissue injury, allergy and cardiovascular melanoma cells to lymph nodes. Here, we show that some diseases as well as in malignant tumors. Chemokine human colon cancer cell lines express CXCR3 constitu- receptor CXCR3 is essential for the physiologic and tively. We constructed cells that expressed CXCR3 cDNA pathologic recruitment of plasmacytoid dendritic cell (‘DLD-1-CXCR3’), and compared with nonexpressing precursors, monocytes and natural killer cells to controls by rectal transplantation in nude mice. Although inflamed lymph nodes (LNs) (Cella et al., 1999; both cell lines disseminated to lymph nodes at similar Janatpour et al., 2001; Martin-Fontecha et al., 2004), frequencies at 2 weeks, DLD-1-CXCR3 expanded more and for retention of Th1 lymphocytes within LNs rapidly than the control in 4 weeks.
    [Show full text]
  • (CS-ⅣA-Be), a Novel IL-6R Antagonist, Inhibits IL-6/STAT3
    Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Chikusetsusaponin Ⅳa butyl ester (CS-Ⅳa-Be), a novel IL-6R antagonist, inhibits IL-6/STAT3 signaling pathway and induces cancer cell apoptosis Jie Yang 1, 2, Shihui Qian 2, Xueting Cai 1, 2, Wuguang Lu 1, 2, Chunping Hu 1, 2, * Xiaoyan Sun1, 2, Yang Yang1, 2, Qiang Yu 3, S. Paul Gao 4, Peng Cao 1, 2 1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China 2. Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China 3. Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China 4. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY10065, USA Running title: CS-Ⅳa-Be, a novel IL-6R antagonist, inhibits IL-6/STAT3 Keywords: Chikusetsusaponin Ⅳ a butyl ester (CS- Ⅳ a-Be), STAT3, IL-6R, antagonist, cancer Grant support: P. Cao received Jiangsu Province Funds for Distinguished Young Scientists (BK20140049) grant, J. Yang received National Natural Science Foundation of China (No. 81403151) grant, and X.Y. Sun received National Natural Science Foundation of China (No. 81202576) grant. Corresponding author: Peng Cao Institute: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China Mailing address: 100#, Shizi Street, Hongshan Road, Nanjing, Jiangsu, China Tel: +86-25-85608666 Fax: +86-25-85608666 Email address: [email protected] The first co-authors: Jie Yang and Shihui Qian The authors disclose no potential conflicts of interest.
    [Show full text]
  • BCMA-Targeted Immunotherapy for Multiple Myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2*
    Yu et al. Journal of Hematology & Oncology (2020) 13:125 https://doi.org/10.1186/s13045-020-00962-7 REVIEW Open Access BCMA-targeted immunotherapy for multiple myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2* Abstract B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development. Keywords: B cell maturation antigen, BCMA, Belantamab mafodotin, CAR-T, Antibody-drug conjugate, Bispecific T cell engager Introduction B cell maturation antigen (BCMA) Recent advances in novel therapeutics such as prote- BCMA is encoded by a 2.92-kb TNFRSF17 gene located asome inhibitors (PI) and immunomodulatory drugs on the short arm of chromosome 16 (16p13.13) and (IMiD) have significantly improved the treatment out- composed of 3 exons separated by 2 introns (Fig. 1). comes in patients with multiple myeloma (MM) [1–8]. BCMA is a 184 amino acid and 20.2-kDa type III trans- However, most MM patients eventually relapse due to membrane glycoprotein, with the extracellular N the development of drug resistance [9]. In addition, terminus containing a conserved motif of 6 cysteines many of the current popular target antigens, such as [18–21].
    [Show full text]
  • OSCAR Is a Receptor for Surfactant Protein D That Activates TNF- Α Release from Human CCR2 + Inflammatory Monocytes
    OSCAR Is a Receptor for Surfactant Protein D That Activates TNF- α Release from Human CCR2 + Inflammatory Monocytes This information is current as Alexander D. Barrow, Yaseelan Palarasah, Mattia Bugatti, of September 25, 2021. Alex S. Holehouse, Derek E. Byers, Michael J. Holtzman, William Vermi, Karsten Skjødt, Erika Crouch and Marco Colonna J Immunol 2015; 194:3317-3326; Prepublished online 25 February 2015; Downloaded from doi: 10.4049/jimmunol.1402289 http://www.jimmunol.org/content/194/7/3317 Supplementary http://www.jimmunol.org/content/suppl/2015/02/24/jimmunol.140228 http://www.jimmunol.org/ Material 9.DCSupplemental References This article cites 40 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/194/7/3317.full#ref-list-1 Why The JI? Submit online. by guest on September 25, 2021 • 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology OSCAR Is a Receptor for Surfactant Protein D That Activates TNF-a Release from Human CCR2+ Inflammatory Monocytes Alexander D.
    [Show full text]
  • HIV-1 Tat Protein Mimicry of Chemokines
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 13153–13158, October 1998 Immunology HIV-1 Tat protein mimicry of chemokines ADRIANA ALBINI*, SILVANO FERRINI*, ROBERTO BENELLI*, SABRINA SFORZINI*, DANIELA GIUNCIUGLIO*, MARIA GRAZIA ALUIGI*, AMANDA E. I. PROUDFOOT†,SAMI ALOUANI†,TIMOTHY N. C. WELLS†, GIULIANO MARIANI‡,RONALD L. RABIN§,JOSHUA M. FARBER§, AND DOUGLAS M. NOONAN*¶ *Centro di Biotecnologie Avanzate, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; †Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, 14 chemin des Aulx, 1228 Plan-les Ouates, Geneva, Switzerland; ‡Dipartimento di Medicina Interna, Medicina Nucleare, University of Genova, Viale Benedetto XV, 6, 16132 Genoa, Italy; and §National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N228 MSC 1888, Bethesda, MD 20892 Edited by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved August 25, 1998 (received for review June 24, 1998) ABSTRACT The HIV-1 Tat protein is a potent chemoat- ceptors for some dual tropic HIV-1 strains (10, 11). A CCR2 tractant for monocytes. We observed that Tat shows conserved polymorphism has been found to correlate with delayed amino acids corresponding to critical sequences of the che- progression to AIDS (12, 13). mokines, a family of molecules known for their potent ability We report here that the HIV-1 Tat protein and the peptide to attract monocytes. Synthetic Tat and a peptide (CysL24–51) encompassing the cysteine-rich and core regions induce per- encompassing the ‘‘chemokine-like’’ region of Tat induced a tussis toxin sensitive Ca21 fluxes in monocytes.
    [Show full text]
  • CCR2 Enhances CD25 Expression by Foxp3+ Regulatory T Cells and Regulates Their Abundance Independently of Chemotaxis and CCR2+ Myeloid Cells
    Cellular & Molecular Immunology www.nature.com/cmi ARTICLE CCR2 enhances CD25 expression by FoxP3+ regulatory T cells and regulates their abundance independently of chemotaxis and CCR2+ myeloid cells Yifan Zhan 1,2,3, Nancy Wang 4, Ajithkumar Vasanthakumar1,2,4, Yuxia Zhang3, Michael Chopin1,2, Stephen L. Nutt 1,2, Axel Kallies1,2,4 and Andrew M. Lew1,2,4 A wide array of chemokine receptors, including CCR2, are known to control Treg migration. Here, we report that CCR2 regulates Tregs beyond chemotaxis. We found that CCR2 deficiency reduced CD25 expression by FoxP3+ Treg cells. Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type (WT) and CCR2−/− strains. Thus, CCR2 deficiency resulted in profound loss of CD25hi FoxP3+ Tregs in secondary lymphoid organs as well as in peripheral tissues. CCR2−/− Treg cells were also functionally inferior to WT cells. Interestingly, these changes to Treg cells did not depend on CCR2+ monocytes/moDCs (the cells where CCR2 receptors are most abundant). Rather, we demonstrated that CCR2 was required for TLR- stimulated, but not TCR- or IL-2-stimulated, CD25 upregulation on Treg cells. Thus, we propose that CCR2 signaling can increase the fitness of FoxP3+ Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells. Cellular & Molecular Immunology (2020) 17:123–132; https://doi.org/10.1038/s41423-018-0187-8 INTRODUCTION production by T cells. Beyond chemotaxis, no other role has been CCR2 is a chemokine receptor known for its role in monocyte ascribed to CCR2 in Tregs.
    [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]
  • The Role of Caspase-2 in Regulating Cell Fate
    cells Review The Role of Caspase-2 in Regulating Cell Fate Vasanthy Vigneswara and Zubair Ahmed * Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK; [email protected] * Correspondence: [email protected] Received: 15 April 2020; Accepted: 12 May 2020; Published: 19 May 2020 Abstract: Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation of caspase-2 to mediate multiple cellular processes far beyond apoptotic cell death. This review provides a comprehensive overview of the literature pertaining to possible sophisticated molecular mechanisms underlying the multifaceted process of caspase-2 activation and to highlight its interplay between factors that promote or suppress apoptosis in a complicated regulatory network that determines the fate of a cell from its birth and throughout its life. Keywords: caspase-2; procaspase; apoptosis; splice variants; activation; intrinsic; extrinsic; neurons 1. Introduction Apoptosis, or programmed cell death (PCD), plays a pivotal role during embryonic development through to adulthood in multi-cellular organisms to eliminate excessive and potentially compromised cells under physiological conditions to maintain cellular homeostasis [1]. However, dysregulation of the apoptotic signaling pathway is implicated in a variety of pathological conditions. For example, excessive apoptosis can lead to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, whilst insufficient apoptosis results in cancer and autoimmune disorders [2,3]. Apoptosis is mediated by two well-known classical signaling pathways, namely the extrinsic or death receptor-dependent pathway and the intrinsic or mitochondria-dependent pathway.
    [Show full text]
  • Human Th17 Cells Share Major Trafficking Receptors with Both Polarized Effector T Cells and FOXP3+ Regulatory T Cells
    Human Th17 Cells Share Major Trafficking Receptors with Both Polarized Effector T Cells and FOXP3+ Regulatory T Cells This information is current as Hyung W. Lim, Jeeho Lee, Peter Hillsamer and Chang H. of September 28, 2021. Kim J Immunol 2008; 180:122-129; ; doi: 10.4049/jimmunol.180.1.122 http://www.jimmunol.org/content/180/1/122 Downloaded from References This article cites 44 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/180/1/122.full#ref-list-1 http://www.jimmunol.org/ 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 by guest on September 28, 2021 *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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Th17 Cells Share Major Trafficking Receptors with Both Polarized Effector T Cells and FOXP3؉ Regulatory T Cells1 Hyung W. Lim,* Jeeho Lee,* Peter Hillsamer,† and Chang H. Kim2* It is a question of interest whether Th17 cells express trafficking receptors unique to this Th cell lineage and migrate specifically to certain tissue sites.
    [Show full text]
  • (P -Value<0.05, Fold Change≥1.4), 4 Vs. 0 Gy Irradiation
    Table S1: Significant differentially expressed genes (P -Value<0.05, Fold Change≥1.4), 4 vs. 0 Gy irradiation Genbank Fold Change P -Value Gene Symbol Description Accession Q9F8M7_CARHY (Q9F8M7) DTDP-glucose 4,6-dehydratase (Fragment), partial (9%) 6.70 0.017399678 THC2699065 [THC2719287] 5.53 0.003379195 BC013657 BC013657 Homo sapiens cDNA clone IMAGE:4152983, partial cds. [BC013657] 5.10 0.024641735 THC2750781 Ciliary dynein heavy chain 5 (Axonemal beta dynein heavy chain 5) (HL1). 4.07 0.04353262 DNAH5 [Source:Uniprot/SWISSPROT;Acc:Q8TE73] [ENST00000382416] 3.81 0.002855909 NM_145263 SPATA18 Homo sapiens spermatogenesis associated 18 homolog (rat) (SPATA18), mRNA [NM_145263] AA418814 zw01a02.s1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE:767978 3', 3.69 0.03203913 AA418814 AA418814 mRNA sequence [AA418814] AL356953 leucine-rich repeat-containing G protein-coupled receptor 6 {Homo sapiens} (exp=0; 3.63 0.0277936 THC2705989 wgp=1; cg=0), partial (4%) [THC2752981] AA484677 ne64a07.s1 NCI_CGAP_Alv1 Homo sapiens cDNA clone IMAGE:909012, mRNA 3.63 0.027098073 AA484677 AA484677 sequence [AA484677] oe06h09.s1 NCI_CGAP_Ov2 Homo sapiens cDNA clone IMAGE:1385153, mRNA sequence 3.48 0.04468495 AA837799 AA837799 [AA837799] Homo sapiens hypothetical protein LOC340109, mRNA (cDNA clone IMAGE:5578073), partial 3.27 0.031178378 BC039509 LOC643401 cds. [BC039509] Homo sapiens Fas (TNF receptor superfamily, member 6) (FAS), transcript variant 1, mRNA 3.24 0.022156298 NM_000043 FAS [NM_000043] 3.20 0.021043295 A_32_P125056 BF803942 CM2-CI0135-021100-477-g08 CI0135 Homo sapiens cDNA, mRNA sequence 3.04 0.043389246 BF803942 BF803942 [BF803942] 3.03 0.002430239 NM_015920 RPS27L Homo sapiens ribosomal protein S27-like (RPS27L), mRNA [NM_015920] Homo sapiens tumor necrosis factor receptor superfamily, member 10c, decoy without an 2.98 0.021202829 NM_003841 TNFRSF10C intracellular domain (TNFRSF10C), mRNA [NM_003841] 2.97 0.03243901 AB002384 C6orf32 Homo sapiens mRNA for KIAA0386 gene, partial cds.
    [Show full text]
  • Cytokine Modulators As Novel Therapies for Airway Disease
    Copyright #ERS Journals Ltd 2001 Eur Respir J 2001; 18: Suppl. 34, 67s–77s European Respiratory Journal DOI: 10.1183/09031936.01.00229901 ISSN 0904-1850 Printed in UK – all rights reserved ISBN 1-904097-20-0 Cytokine modulators as novel therapies for airway disease P.J. Barnes Cytokine modulators as novel therapies for airway disease. P.J. Barnes. #ERS Correspondence: P.J. Barnes Journals Ltd 2001. Dept of Thoracic Medicine ABSTRACT: Cytokines play a critical role in orchestrating and perpetuating National Heart & Lung Institute inflammation in asthma and chronic obstructive pulmonary disease (COPD), and Imperial College Dovehouse Street several specific cytokine and chemokine inhibitors are now in development for the future London SW3 6LY therapy of these diseases. UK Anti-interleukin (IL)-5 is very effective at reducing peripheral blood and airway Fax: 0207 3515675 eosinophil numbers, but does not appear to be effective against symptomatic asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in Keywords: Chemokine receptor asthma. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, cytokine as systemic delivery causes side-effects. Inhibition of tumour necrosis factor-a may be interleukin-4 useful in severe asthma and for treating severe COPD with systemic features. interleukin-5 interleukin-9 Many chemokines are involved in the inflammatory response of asthma and COPD interleukin-10 and several low-molecular-weight inhibitors of chemokine receptors are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which Received: March 26 2001 block neutrophil and monocyte chemotaxis) are in clinical development for the Accepted April 25 2001 treatment of asthma and COPD respectively.
    [Show full text]