Is BOK Required for Apoptosis Induced by Endoplasmic Reticulum Stress?
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Download.Cse.Ucsc.Edu/ Early Age of Onset (~2.5 Years) of This PRA Form in Goldenpath/Canfam2/Database/) Using Standard Settings
Kropatsch et al. Canine Genetics and Epidemiology (2016) 3:7 DOI 10.1186/s40575-016-0037-x RESEARCH Open Access A large deletion in RPGR causes XLPRA in Weimaraner dogs Regina Kropatsch1*, Denis A. Akkad1, Matthias Frank2, Carsten Rosenhagen3, Janine Altmüller4,5, Peter Nürnberg4,6,7, Jörg T. Epplen1,8 and Gabriele Dekomien1 Abstract Background: Progressive retinal atrophy (PRA) belongs to a group of inherited retinal disorders associated with gradual vision impairment due to degeneration of retinal photoreceptors in various dog breeds. PRA is highly heterogeneous, with autosomal dominant, recessive or X-linked modes of inheritance. In this study we used exome sequencing to investigate the molecular genetic basis of a new type of PRA, which occurred spontaneously in a litter of German short-hair Weimaraner dogs. Results: Whole exome sequencing in two PRA-affected Weimaraner dogs identified a large deletion comprising the first four exons of the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene known to be involved in human retinitis pigmentosa and canine PRA. Screening of 16 individuals in the corresponding pedigree of short-hair Weimaraners by qPCR, verified the deletion in hemizygous or heterozygous state in one male and six female dogs, respectively. The mutation was absent in 88 additional unrelated Weimaraners. The deletion was not detectable in the parents of one older female which transmitted the mutation to her offspring, indicating that the RPGR deletion represents a de novo mutation concerning only recent generations of the Weimaraner breed in Germany. Conclusion: Our results demonstrate the value of an existing DNA biobank combined with exome sequencing to identify the underlying genetic cause of a spontaneously occurring inherited disease. -
Analysis of Trans Esnps Infers Regulatory Network Architecture
Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation. -
BCL-2 Family Proteins: Changing Partners in the Dance Towards Death
Cell Death and Differentiation (2018) 25, 65–80 OPEN Official journal of the Cell Death Differentiation Association www.nature.com/cdd Review BCL-2 family proteins: changing partners in the dance towards death Justin Kale1, Elizabeth J Osterlund1,2 and David W Andrews*,1,2,3 The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis. The affinities and relative abundance of the BCL-2 family proteins dictate the predominate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP. We highlight the core mechanisms of BCL-2 family regulation of MOMP with an emphasis on how the interactions between the BCL-2 family proteins govern cell fate. We address the critical importance of both the concentration and affinities of BCL-2 family proteins and show how differences in either can greatly change the outcome. Further, we explain the importance of using full-length BCL-2 family proteins (versus truncated versions or peptides) to parse out the core mechanisms of MOMP regulation by the BCL-2 family. Finally, we discuss how post- translational modifications and differing intracellular localizations alter the mechanisms of apoptosis regulation by BCL-2 family proteins. Successful therapeutic intervention of MOMP regulation in human disease requires an understanding of the factors that mediate the major binding interactions between BCL-2 family proteins in cells. Cell Death and Differentiation (2018) 25, 65–80; doi:10.1038/cdd.2017.186; published online 17 November 2017 The membrane plays an active role in most BCL-2 family interactions by changing the affinities and local relative abundance of these proteins. -
BCL-2 Family Member BOK Promotes Apoptosis in Response to Endoplasmic Reticulum Stress
BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress Marcos A. Carpioa, Michael Michauda, Wenping Zhoua, Jill K. Fisherb, Loren D. Walenskyb,1, and Samuel G. Katza,1 aDepartment of Pathology, Yale School of Medicine, New Haven, CT 06520; and bDepartment of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 Edited by J. Marie Hardwick, The Johns Hopkins University, Baltimore, MD, and accepted by the Editorial Board April 30, 2015 (received for review November 3, 2014) B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) is a BCL-2 family derived from these mice are equally susceptible to death stimuli (15), − − − − protein with high homology to the multidomain proapoptotic in stark contrast to the severe apoptotic blockade of Bax / Bak / proteins BAX and BAK, yet Bok−/− and even Bax−/−Bok−/− and cells. Also intriguing, a functional role for Bok as a tumor sup- −/− −/− Bak Bok mice were reported to have no overt phenotype or pressor was suggested by its genetic location in 1 of the 20 most apoptotic defects in response to a host of classical stress stimuli. deleted regions in all human cancers (16). These surprising findings were interpreted to reflect functional To investigate a role for BOK in the apoptotic pathway, we −/− compensation among the BAX, BAK, and BOK proteins. However, generated Bok mice and cells. Based on the recent localiza- −/− BOK cannot compensate for the severe apoptotic defects of Bax tion of BOK at the endoplasmic reticulum (ER) (4), we focused −/− Bak mice despite its widespread expression. -
Mouse Mutants As Models for Congenital Retinal Disorders
Experimental Eye Research 81 (2005) 503–512 www.elsevier.com/locate/yexer Review Mouse mutants as models for congenital retinal disorders Claudia Dalke*, Jochen Graw GSF-National Research Center for Environment and Health, Institute of Developmental Genetics, D-85764 Neuherberg, Germany Received 1 February 2005; accepted in revised form 1 June 2005 Available online 18 July 2005 Abstract Animal models provide a valuable tool for investigating the genetic basis and the pathophysiology of human diseases, and to evaluate therapeutic treatments. To study congenital retinal disorders, mouse mutants have become the most important model organism. Here we review some mouse models, which are related to hereditary disorders (mostly congenital) including retinitis pigmentosa, Leber’s congenital amaurosis, macular disorders and optic atrophy. q 2005 Elsevier Ltd. All rights reserved. Keywords: animal model; retina; mouse; gene mutation; retinal degeneration 1. Introduction Although mouse models are a good tool to investigate retinal disorders, one should keep in mind that the mouse Mice suffering from hereditary eye defects (and in retina is somehow different from a human retina, particular from retinal degenerations) have been collected particularly with respect to the number and distribution of since decades (Keeler, 1924). They allow the study of the photoreceptor cells. The mouse as a nocturnal animal molecular and histological development of retinal degener- has a retina dominated by rods; in contrast, cones are small ations and to characterize the genetic basis underlying in size and represent only 3–5% of the photoreceptors. Mice retinal dysfunction and degeneration. The recent progress of do not form cone-rich areas like the human fovea. -
The Apoptosis Database
Cell Death and Differentiation (2003) 10, 621–633 & 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00 www.nature.com/cdd Review The apoptosis database KS Doctor1, JC Reed1, A Godzik1 and PE Bourne*,1,2 Introduction 1 The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, The set of known proteins that directly regulate apoptosis has USA 2 San Diego Supercomputer Center, University of California San Diego, 9500 grown rapidly over the last 15 years. This growth will continue Gilman Drive, La Jolla, CA 92093-0505, USA until all the proteins directly involved in the cell death signaling * Corresponding author: PE Bourne, Tel: 858-534-8301; Fax: 858-822-0873, process are known. This assortment of proteins with wide E-mail: [email protected] ranging biochemical functions is linked together conceptually in the minds of apoptosis researchers. Assembling an up-to- Received 10.9.02; revised 3.12.02; accepted 10.12.02 date view of this conceptual collection of proteins within the Edited by Dr Green context of apoptosis requires a considerable effort, or more specifically, complete immersion into the field. One principal Abstract goal of an apoptosis review article is to assemble such a collection of protein annotations as an educational and The apoptosis database is a public resource for researchers research resource. The apoptosis database described here and students interested in the molecular biology of apoptosis. is designed to fulfil the same goal, but to immediately allow the The resource provides functional annotation, literature user to dig deeper using local and remote information and to references, diagrams/images, and alternative nomenclatures always remain current with respect to the proteins known to be on a set of proteins having ‘apoptotic domains’. -
Effectiveness and Therapeutic Value of Phytochemicals in Acute Pancreatitis: a Review
Pancreatology 19 (2019) 481e487 Contents lists available at ScienceDirect Pancreatology journal homepage: www.elsevier.com/locate/pan Effectiveness and therapeutic value of phytochemicals in acute pancreatitis: A review * Aleksandra Tarasiuk, Jakub Fichna Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Poland article info abstract Article history: Background: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can lead to local Received 31 January 2019 and systemic complications. Repeated attacks of AP can lead to chronic pancreatitis, which markedly Received in revised form increases the probability of developing pancreatic cancer. Although many researchers have attempted to 25 March 2019 identify the pathogenesis involved in the initiation and aggravation of AP, the disease is still not fully Accepted 21 April 2019 understood, and effective treatment is limited to supportive therapy. Available online 3 May 2019 Methods: We aim to summarize available literature focused on phytochemicals (berberine, chlorogenic acid, curcumin, emblica officinalis, ellagic acid, cinnamtannin B-1, resveratrol, piperine and lycopene) Keywords: Acute pancreatitis and discuss their effectiveness and therapeutic value for improving AP. Treatment of acute pancreatitis Results: This study is based on pertinent papers that were retrieved by a selective search using relevant Phytochemicals keywords in PubMed and ScienceDirect databases. Conclusions: Many phytochemicals hold potential in improving AP symptoms and may be a valuable and effective addition to standard treatment of AP. It has already been proven that the crucial factor for reducing the severity of AP is stimulation of apoptosis along with/or inhibition of necrosis. Supple- mentation of phytochemicals, which target the balance between apoptosis and necrosis can be recom- mended in ongoing clinical studies. -
Control of Cell Death/Survival Balance by the MET Dependence Receptor
RESEARCH ARTICLE Control of cell death/survival balance by the MET dependence receptor Leslie Duplaquet1, Catherine Leroy1†, Audrey Vinchent1†, Sonia Paget1, Jonathan Lefebvre1, Fabien Vanden Abeele2, Steve Lancel3, Florence Giffard4, Re´ jane Paumelle3, Gabriel Bidaux5, Laurent Heliot5, Laurent Poulain4, Alessandro Furlan1,5*, David Tulasne1* 1Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, Lille, France; 2Univ. Lille, Inserm, U1003 - PHYCEL - Physiologie Cellulaire, Lille, France; 3Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Lille, France; 4Normandie Universite´, UNICAEN, INSERM U1086 ANTICIPE, UNICANCER, Cancer Centre F. Baclesse, Caen, France; 5Univ. Lille, CNRS, UMR8523 - PhLAM – laboratoire de Physique des Lasers, Atomes et Mole´cules, Lille, France Abstract Control of cell death/survival balance is an important feature to maintain tissue homeostasis. Dependence receptors are able to induce either survival or cell death in presence or absence of their ligand, respectively. However, their precise mechanism of action and their physiological importance are still elusive for most of them including the MET receptor. We evidence that pro-apoptotic fragment generated by caspase cleavage of MET localizes to the mitochondria-associated membrane region. This fragment triggers a calcium transfer from endoplasmic reticulum to mitochondria, which is instrumental for the apoptotic action of the *For correspondence: receptor. Knock-in mice bearing a mutation of MET caspase cleavage site highlighted that p40MET [email protected] (AF); production is important for FAS-driven hepatocyte apoptosis, and demonstrate that MET acts as a [email protected] (DT) dependence receptor in vivo. Our data shed light on new signaling mechanisms for dependence †These authors contributed receptors’ control of cell survival/death balance, which may offer new clues for the pathophysiology equally to this work of epithelial structures. -
Thirty Years of BCL-2: Translating Cell Death Discoveries Into Novel Cancer
PERSPECTIVES normal physiology and cancer remains TIMELINE unclear, and is beyond the scope of this article (for a review on these topics, see Thirty years of BCL-2: translating REF. 10). This Timeline article focuses on key advances in our understanding of the function of the BCL-2 protein family in cell death discoveries into novel cell death, in the development of cancer, cancer therapies and as targets in cancer therapy. Early studies on apoptosis Alex R. D. Delbridge, Stephanie Grabow, Andreas Strasser and David L. Vaux In their 1972 paper that adopted the word ‘apoptosis’ to describe a physiological Abstract | The ‘hallmarks of cancer’ are generally accepted as a set of genetic and process of cellular suicide, Kerr and epigenetic alterations that a normal cell must accrue to transform into a fully colleagues11 recognized the presence malignant cancer. It follows that therapies designed to counter these alterations of apoptotic cells in tissue sections of miht e effective as anti-cancer strateies ver the past 3 years, research on certain human cancers. Accordingly, the BCL-2-regulated apoptotic pathway has led to the development of they proposed that increasing the rate of apoptosis of neoplastic cells relative to their small-molecule compounds, nown as BH3-mimetics, that ind to pro-survival rate of production could potentially be BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline therapeutic. However, interest in cell death article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and its role in cancer languished until the and, specifically, its roles in cancer development and therapy late 1980s, when genetic abnormalities that prevented cell death were directly linked to malignancy in humans. -
Intracellular Localization of the BCL-2 Family Member BOK and Functional Implications
Cell Death and Differentiation (2013) 20, 785–799 & 2013 Macmillan Publishers Limited All rights reserved 1350-9047/13 www.nature.com/cdd Intracellular localization of the BCL-2 family member BOK and functional implications N Echeverry1, D Bachmann1,FKe2,3, A Strasser2,3, HU Simon1 and T Kaufmann*,1 The pro-apoptotic BCL-2 family member BOK is widely expressed and resembles the multi-BH domain proteins BAX and BAK based on its amino acid sequence. The genomic region encoding BOK was reported to be frequently deleted in human cancer and it has therefore been hypothesized that BOK functions as a tumor suppressor. However, little is known about the molecular functions of BOK. We show that enforced expression of BOK activates the intrinsic (mitochondrial) apoptotic pathway in BAX/ BAK-proficient cells but fails to kill cells lacking both BAX and BAK or sensitize them to cytotoxic insults. Interestingly, major portions of endogenous BOK are localized to and partially inserted into the membranes of the Golgi apparatus as well as the endoplasmic reticulum (ER) and associated membranes. The C-terminal transmembrane domain of BOK thereby constitutes a ‘tail-anchor’ specific for targeting to the Golgi and ER. Overexpression of full-length BOK causes early fragmentation of ER and Golgi compartments. A role for BOK on the Golgi apparatus and the ER is supported by an abnormal response of Bok-deficient cells to the Golgi/ER stressor brefeldin A. Based on these results, we propose that major functions of BOK are exerted at the Golgi and ER membranes and that BOK induces apoptosis in a manner dependent on BAX and BAK. -
Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss
cells Review Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss 1, 1, 1 1,2,3 1 Gayle B. Collin y, Navdeep Gogna y, Bo Chang , Nattaya Damkham , Jai Pinkney , Lillian F. Hyde 1, Lisa Stone 1 , Jürgen K. Naggert 1 , Patsy M. Nishina 1,* and Mark P. Krebs 1,* 1 The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; [email protected] (G.B.C.); [email protected] (N.G.); [email protected] (B.C.); [email protected] (N.D.); [email protected] (J.P.); [email protected] (L.F.H.); [email protected] (L.S.); [email protected] (J.K.N.) 2 Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand 3 Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand * Correspondence: [email protected] (P.M.N.); [email protected] (M.P.K.); Tel.: +1-207-2886-383 (P.M.N.); +1-207-2886-000 (M.P.K.) These authors contributed equally to this work. y Received: 29 February 2020; Accepted: 7 April 2020; Published: 10 April 2020 Abstract: Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. -
Bok Is a Genuine Multi-BH-Domain Protein That Triggers Apoptosis in The
© 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 3054 doi:10.1242/jcs.193946 CORRECTION Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak Stephanie Einsele-Scholz, Silke Malmsheimer, Katrin Bertram, Daniel Stehle, Janina Johänning, Marianne Manz, Peter T. Daniel, Bernhard F. Gillissen, Klaus Schulze-Osthoff and Frank Essmann There was an error published in J. Cell Sci. 129, 2213–2223. In Fig. 4A, a statement that duplicate α-tubulin blots are shown for Mcl-1 and Bok, and for caspase-3 and Bax, because the same membranes were probed for these proteins, was inadvertently omitted from the legend. The authors apologise to the readers for any confusion that this error might have caused. Journal of Cell Science 3054 © 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 2213-2223 doi:10.1242/jcs.181727 RESEARCH ARTICLE Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak Stephanie Einsele-Scholz1, Silke Malmsheimer1, Katrin Bertram1, Daniel Stehle1, Janina Johänning1, Marianne Manz1, Peter T. Daniel2,3, Bernhard F. Gillissen2,3, Klaus Schulze-Osthoff1,3,* and Frank Essmann1,3,* ABSTRACT Mcl-1 and A1 (also known as BCL2A1) (Chi et al., 2014). The anti- The pro-apoptotic multidomain Bcl-2 proteins Bax and Bak (also apoptotic Bcl-2 proteins can be inhibited in turn by a third subgroup, known as BAK1) are considered the gatekeepers of the intrinsic the Bcl-2 homology domain 3 (BH3)-only proteins, such as Bad, pathway of apoptosis by triggering the mitochondrial release of Bid, Bik (also known as Nbk), Bim (also known as BCL2L11), cytochrome c.