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  • 1.
    Alexander, Helen K.
    et al.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Booy, Evan P.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Xiao, Wenyan
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Ezzati, Peyman
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Baust, Heinrich
    Department of Radiooncology, University of Erlangen, Erlangen, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Selected technologies to control genes and their products for experimental and clinical purposes2007In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 55, no 3, p. 139-149Article in journal (Refereed)
    Abstract [en]

    "On-demand" regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch (R), coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the "Dual Drug Control" system, "constitutive androstane receptor"-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.

  • 2.
    Booy, Evan P.
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Johar, Dina
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Maddika, Srilekha
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Pirzada, Hasan
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Sahib, Mickey M.
    Department of Oral Biology, University of Manitoba, Winnipeg, Canada .
    Gehrke, Iris
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Loewen, Shauna
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Louis, Sherif F.
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Kadkhoda, Kamran
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Mowat, Michael
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Monoclonal and bispecific antibodies as novel therapeutics2006In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 54, no 2, p. 85-101Article in journal (Refereed)
    Abstract [en]

    Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodies" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.

  • 3.
    Cassens, U.
    et al.
    Institute of Transfusion Medicine, University of Münster, D-48149 Münster, Germany.
    Lewinski, G.
    Unit of Surgery, Municipal Hospital, 38-300 Gorlice, Poland.
    Samraj, A. K.
    Institute of Molecular Medicine, University of Düsseldorf, D-40225 Düsseldorf, Germany.
    von Bernuth, H.
    Children´s University Clinic, Laboratory for Clinical Research, D-01307 Dresden, Germany.
    Baust, H.
    Department of Radiotherapy, University of Ulm, D-89070 Ulm, Germany.
    Khazaie, K.
    Department of Cancer Immunology and Aids, Dana Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Viral modulation of cell death by inhibition of caspases2003In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 51, no 1, p. 19-27Article, review/survey (Refereed)
    Abstract [en]

    Caspases are key effectors of the apoptotic process. Some of them play important roles in the immune system, being involved in the proteolytic maturation of the key cytokines, including interleukin 1beta (IL-1beta) and IL-18. The latter directs the production of interferon gamma (IFN-gamma). Among pathogens, particularly viruses express various modulators of caspases that inhibit their activity by direct binding. By evading the apoptotic process, viruses can better control their production in the infected cell and avoid the attack of the immune system. Targeting the maturation of the key cytokines involved in the initiation of (antiviral) immune response helps to avoid recognition and eradication by the immune system. The three main classes of caspase inhibitors frequently found among viruses include serine proteinase inhibitors (serpins: CrmA/SPI-2), viral IAPs (vIAPs) and p35. Their molecular mechanisms of action, structures and overall influence on cellular physiology are discussed in the review below.

  • 4.
    Chaabane, Wiem
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    User, Sirma D.
    Middle East Technical University, Ankara, Turkey .
    El-Gazzah, Mohamed
    Tunis University, Tunisia .
    Jaksik, Roman
    Silesian University of Technology, Gliwice, Poland.
    Sajjadi, Elaheh
    Tehran University of Medical Sciences, Iran .
    Rzeszowska-Wolny, Joanna
    Silesian University of Technology, Gliwice, Poland.
    Łos, Marek J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer2013In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 61, no 1, p. 43-58Article, review/survey (Refereed)
    Abstract [en]

    Cell death is a fundamental ingredient of life. Thus, not surprisingly more than one form of cell death exists. Several excellent reviews on various forms of cell death have already been published but manuscripts describing interconnection and interdependence between such processes are uncommon. Here, what follows is a brief introduction on all three classical forms of cell death, followed by a more detailed insight into the role of p53, the master regulator of apoptosis, and other forms of cell death. While discussing p53 and also the role of caspases in cell death forms, we offer insight into the interplay between autophagy and apoptosis, or necrosis, where autophagy may initially serve pro-survival functions. The review moves further to present some details about less researched forms of programmed cell death, namely necroptosis, necrosis and mitoptosis. These “mixed” forms of cell death allow us to highlight the interconnected nature of cell death forms, particularly apoptosis and necrosis. The interdependence between apoptosis, autophagy and necrosis, and their significance for cancer development and treatment are also analyzed in further parts of the review. In the concluding parts, the afore-mentioned issues will be put in perspective for the development of novel anti-cancer therapies.

  • 5.
    Hauff, K.
    et al.
    Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Zamzow, C.
    Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
    Law, W. J.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    De Melo, J.
    Department of Anatomy, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Kennedy, K.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system2005In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 53, no 4, p. 308-320Article in journal (Refereed)
    Abstract [en]

    In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood-brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase-1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.

  • 6.
    Hombach-Klonisch, Sabine
    et al.
    Department Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada .
    Paranjothy, Ted
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada .
    Wiechec, Emilia
    Department of Human Genetics, University of Aarhus, Aarhus, Denmark.
    Pocar, Paola
    Department of Animal Science, Faculty of Veterinary Medicine, University of Milan, Milan, Italy .
    Mustafa, Tarek
    Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, University Magdeburg, Magdeburg, Germany; Experimental Surgery and Oncology Research Group, Department of General, Visceral and Vascular Surgery, University of Halle-Wittenberg, Halle, Germany .
    Seifert, Anja
    Department Anatomy and Cell Biology, University of Halle-Wittenberg, Halle, Germany .
    Zahl, Christian
    Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, University Magdeburg, Magdeburg, Germany .
    Luis Gerlach, Klaus
    Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, University Magdeburg, Magdeburg, Germany .
    Biermann, Katharina
    Institute of Pathology, University Hospital Bonn, Bonn, Germany .
    Steger, Klaus
    Department of Urology and Pediatric Urology, University of Giessen, Giessen, Germany .
    Hoang-Vu, Cuong
    Experimental Surgery and Oncology Research Group, Department of General, Visceral and Vascular Surgery, University of Halle-Wittenberg, Halle, Germany .
    Schulze-Osthoff, Klaus
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada; BioApplications Enterprises, Winnipeg, MB, Canada.
    Cancer stem cells as targets for cancer therapy: selected cancers as examples2008In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 56, no 3, p. 165-180Article, review/survey (Refereed)
    Abstract [en]

    It is becoming increasingly evident that cancer constitutes a group of diseases involving altered stem-cell maturation/differentiation and the disturbance of regenerative processes. The observed malignant transformation is merely a symptom of normal differentiation processes gone astray rather than the primary event. This review focuses on the role of cancer stem cells (CSCs) in three common but also relatively under-investigated cancers: head and neck, ovarian, and testicular cancer. For didactic purpose, the physiology of stem cells is first introduced using hematopoietic and mesenchymal stem cells as examples. This is followed by a discussion of the (possible) role of CSCs in head and neck, ovarian, and testicular cancer. Aside from basic information about the pathophysiology of these cancers, current research results focused on the discovery of molecular markers specific to these cancers are also discussed. The last part of the review is largely dedicated to signaling pathways active within various normal and CSC types (e.g. Nanog, Nestin, Notch1, Notch2, Oct3 and 4, Wnt). Different elements of these pathways are also discussed in the context of therapeutic opportunities for the development of targeted therapies aimed at CSCs. Finally, alternative targeted anticancer therapies arising from recently identified molecules with cancer-(semi-)selective capabilities (e.g. apoptin, Brevinin-2R) are considered.

  • 7.
    Kreuter, M.
    et al.
    Department of Medicine/Hematology and Oncology, Muenster, Germany.
    Langer, C.
    Central Clinical Laboratory, Medical Clinic, Muenster, Germany.
    Kerkhoff, C.
    Institute of Experimental Dermatology, University of Muenster, Germany.
    Reddanna, P.
    School of Life Sciences, University of Hyderabad, India.
    Kania, A. L.
    Manitoba Institute of Cell Biology, Winnipeg, Canada.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada; School of Life Sciences, University of Hyderabad, India .
    Chlichlia, K.
    Department of Tropical Hygiene, University of Heidelberg, Heidelberg, Germany.
    Bui, T. N.
    Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
    Los, Marek Jan
    Institute of Experimental Dermatology, University of Muenster, Germany; Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development2004In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 52, no 3, p. 141-155Article, review/survey (Refereed)
    Abstract [en]

    Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models For drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, 1 when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders Such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.

  • 8.
    Likus, Wirginia
    et al.
    Medical University of Silesia, Poland.
    Siemianowicz, Krzysztof
    Medical University of Silesia, Poland.
    Markowski, Jaroslaw
    Medical University of Silesia, Poland.
    Wiaderkiewicz, Jan
    Medical University of Silesia, Poland; George Washington University, DC USA.
    Kostrzab-Zdebel, Anna
    Medical University of Silesia, Poland.
    Jura-Szoltys, Edyta
    Medical University of Silesia, Poland.
    Dziubdziela, Wlodzimierz
    Outpatient Clin Treatment Chron Pain, Poland.
    Wiaderkiewicz, Ryszard
    Medical University of Silesia, Poland.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Pomeranian Medical University, Poland.
    Bacterial Infections and Osteoclastogenesis Regulators in Men and Women with Cholesteatoma2016In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 64, no 3, p. 241-247Article, review/survey (Refereed)
    Abstract [en]

    One of the most distinct features of middle ear cholesteatoma is bone destruction. Aetiology of cholesteatoma is thought to be multifactorial. Endotoxins produced by bacteria are thought to initiate the inflammation process in the middle ear leading to cholesteatoma. There are physiological differences in bone metabolism between men and women. The aim of our study was the immunohistochemical evaluation of the contents of two key components of the OPG/RANK/RANKL triad-RANKL and OPG in cholesteatoma, to analyse if there are any differences between the sexes and to evaluate the bacteria species isolated from cholesteatoma just before surgical treatment and to evaluate their plausible influence on the expression of OPG and RANKL in cholesteatoma. Twenty-one adult patients with acquired cholesteatoma who underwent surgery were analysed. There were no statistically significant differences in the expression of both regulators of osteoclastogenesis between the sexes. In 38.1 % patients cholesteatoma was not infected, whereas in 61.9 % patients various bacterial infections or mycosis were found. The most frequently isolated species was Pseudomonas aeruginosa (14.29 % infections) followed by Staphylococcus aureus (9.52 % infections). There were no statistically significant differences in expression of both OPG and RANKL between uninfected and infected cholesteatomas.

  • 9.
    Mendoza, F. J.
    et al.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    Espino, P. S.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    Cann, K. L.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    Bristow, N.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    McCrea, K.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Anti-tumor chemotherapy utilizing peptide-based approaches - apoptotic pathways, kinases, and proteasome as targets2005In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 53, no 1, p. 47-60Article in journal (Refereed)
    Abstract [en]

    The pharmacological sciences are taking advantage of recent discoveries that have defined the molecular pathways governing apoptosis. These signaling cascades are frequently inactivated or distorted by mutations in cancer cells. Peptides derived from critical interaction, phosphorylation, or cleavage sites are the preferred leads (starting points) for the development of new drugs. In this review we summarize recent peptide-based approaches that target MDM2, p53, NF-kappaB, ErbB2, MAPK, as well as Smac/DIABLO, IAP BIR domains, and Bcl-2 interaction domains, with a specific focus on the BH3 domain. Separate parts of the review deal with proteasome inhibitors, integrin-derived peptides, and molecules that are being tested for tumor-selective delivery of anticancer drugs ("magic bullet" approach). The proteasome inhibitors and integrin-derived peptides show a variety of effects, targeting not only tumor growth, but also angiogenesis, metastasizing potential, and other cancer cell functions. The last part of this review describes approaches that use specific properties (surface receptors, increased enzymatic activities) of cancer cells in order to target them specifically. These new generations of anticancer drugs provide the foundations for therapies with fewer side effects and higher efficacy.

  • 10.
    Sadowski-Debbing, K.
    et al.
    Clinic for Craniomaxillofacial Surgery, Ahaus, Germany.
    Coy, J. F.
    MTM Laboratories AG, Im Neuenheimer Feld 519, D-69120 Heidelberg, Germany.
    Mier, W.
    Institute of Nuclear Medicine, University of Heidelberg, D-69120 Heidelberg, Germany.
    Hug, H.
    University Childrens Hospital, Prittwitzstr. 43, D-89075 Ulm, Germany.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of M uenster D-48149 Muenster, Germany.
    Caspases - Their role in apoptosis and other physiological processes as revealed by knock-out studies2002In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 50, no 1, p. 19-34Article, review/survey (Refereed)
    Abstract [en]

    Caspases are crucial mediators of apoptosis, a form of physiological cell death. Their activation is carefully controlled by a philogenetically conserved death program, which is indispensable for the homeostasis and development of higher organisms. Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. In vitro studies have demonstrated the requirement of caspase activity for both the triggering phase as well as the execution of apoptosis, thus providing a molecular base for the time-tuning of this process by pharmacological agents. The precise roles of the individual caspases in vivo and their functional relation to each other have been best demonstrated in genetically modified animals. The generation of single caspase-deficient mice have confirmed most of the data obtained in vitro and exposed some new aspects previously undetected in the cell culture system. Interestingly, inactivation of many caspases revealed not only their expected participation in apoptotic events as well as in the maturation of cytokines, but also provided hints about the role of at least some caspases in cell differentiation and stimulatory responses. In this review we will discuss what these studies have unveiled about the role of individual caspases in development, apoptosis, and inflammation, with particular focus on their role beyond the apoptotic process.

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