Blog
About

6
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      TRAIL-Induced Apoptosis in Human Vascular Endothelium Is Regulated by Phosphatidylinositol 3-Kinase/Akt through the Short Form of Cellular FLIP and Bcl-2

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background: Apoptosis of vascular endothelial cells plays a central role in angiogenesis and atherosclerosis. This study investigates the molecular mechanisms of endothelial apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following inhibition of phosphatidylinositol 3-kinase (PI3K). It examines downstream regulation and activation of the extrinsic and intrinsic pathways. Methods and Results: By flow cytometry, TRAIL receptors 2 and 3 were present to a greater extent than receptors 1 and 4. TRAIL reduced cell numbers in combination with the PI3K inhibitor LY 294002. TRAIL (100 ng/ml) with LY 294002 (20 µmol/l) activated the extrinsic pathway, causing progressive cleavage of caspase-8 and caspase-3. Activation of the intrinsic pathway proceeded by release of mitochondrial factors Smac/DIABLO and cytochrome c, and caspase-9 cleavage. LY 294002 reduced phosphorylated Akt (p-Akt), with early loss of the short form of cellular FLIP (c-FLIP<sub>S</sub>) and concurrent reduction of Bcl-2. Treatment with small interfering RNA against PI3K also reduced c-FLIP<sub>S</sub> and Bcl-2, and cotreatment with TRAIL triggered caspase-3 cleavage. Conclusions: This study details the molecular regulation of TRAIL-induced apoptosis in vascular endothelium. Inhibition of PI3K reduces p-Akt, with concurrent reductions in c-FLIP<sub>S</sub> and Bcl-2, and so renders endothelium sensitive to TRAIL-induced apoptosis through the extrinsic and intrinsic pathways.

          Related collections

          Most cited references 42

          • Record: found
          • Abstract: not found
          • Article: not found

          Cellular survival: a play in three Akts.

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Inhibition of death receptor signals by cellular FLIP.

            The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis. However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals, indicating that inhibitors of the apoptosis-signalling pathway must exist. Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues. The short form, FLIPs, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis, whereas the long form, FLIP(L), contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIPs and FLIP(L) interact with the adaptor protein FADD and the protease FLICE, and potently inhibit apoptosis induced by all known human death receptors. FLIP(L) is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis. High levels of FLIP(L) protein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Oxidative stress as a mediator of apoptosis.

              Many agents which induce apoptosis are either oxidants or stimulators of cellular oxidative metabolism. Conversely, many inhibitors of apoptosis have antioxidant activities or enhance cellular antioxidant defenses. Mammalian cells exist in a state of oxidative siege in which survival requires an appropriate balance of oxidants and antioxidants. Thomas Buttke and Paul Sandstrom suggest that eukaryotic cells may benefit from this perilous existence by invoking oxidative stress as a common mediator of apoptosis.
                Bookmark

                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2005
                August 2005
                29 July 2005
                : 42
                : 4
                : 337-347
                Affiliations
                Departments of aLaboratory Medicine and Pathology, bPhysiology and cObstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
                Article
                86599 J Vasc Res 2005;42:337–347
                10.1159/000086599
                15985761
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, References: 69, Pages: 11
                Categories
                Research Paper

                Comments

                Comment on this article