DOCSLIB.ORG

Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity Through BECN1 and Promotes an Autophagy-Associated Necrosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity Through BECN1 and Promotes an Autophagy-Associated Necrosis Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity through BECN1 and Promotes an Autophagy-Associated Necrosis Anatasha C. Crawford, Rebecca B. Riggins, Ayesha N. Shajahan, Alan Zwart, Robert Clarke* Lombardi Comprehensive Cancer Center and Department of Oncology, School of Medicine, Georgetown University, Washington, District of Columbia, United States of America Abstract BCL2 family members affect cell fate decisions in breast cancer but the role of BCL-W (BCL2L2) is unknown. We now show the integrated roles of the antiapoptotic BCL-W and BCL2 in affecting responsiveness to the antiestrogen ICI 182,780 (ICI; Fulvestrant Faslodex), using both molecular (siRNA; shRNA) and pharmacologic (YC137) approaches in three breast cancer variants; MCF-7/LCC1 (ICI sensitive), MCF-7/LCC9 (ICI resistant), and LY2 (ICI resistant). YC137 inhibits BCL-W and BCL2 and restores ICI sensitivity in resistant cells. Co-inhibition of BCL-W and BCL2 is both necessary and sufficient to restore sensitivity to ICI, and explains mechanistically the action of YC137. These data implicate functional cooperation and/or redundancy in signaling between BCL-W and BCL2, and suggest that broad BCL2 family member inhibitors will have greater therapeutic value than targeting only individual proteins. Whereas ICI sensitive MCF-7/LCC1 cells undergo increased apoptosis in response to ICI following BCL-W6BCL2 co-inhibition, the consequent resensitization of resistant MCF-7/LCC9 and LY2 cells reflects increases in autophagy (LC3 cleavage; p62/SQSTM1 expression) and necrosis but not apoptosis or cell cycle arrest. Thus, de novo sensitive cells and resensitized resistant cells die through different mechanisms. Following BCL-W+BCL2 co-inhibition, suppression of functional autophagy by 3-methyladenine or BECN1 shRNA reduces ICI-induced necrosis but restores the ability of resistant cells to die through apoptosis. These data demonstrate the plasticity of cell fate mechanisms in breast cancer cells in the context of antiestrogen responsiveness. Restoration of ICI sensitivity in resistant cells appears to occur through an increase in autophagy-associated necrosis. BCL-W, BCL2, and BECN1 integrate important functions in determining antiestrogen responsiveness, and the presence of functional autophagy may influence the balance between apoptosis and necrosis. Citation: Crawford AC, Riggins RB, Shajahan AN, Zwart A, Clarke R (2010) Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity through BECN1 and Promotes an Autophagy-Associated Necrosis. PLoS ONE 5(1): e8604. doi:10.1371/journal.pone.0008604 Editor: Mikhail V. Blagosklonny, Roswell Park Cancer Institute, United States of America Received November 11, 2009; Accepted December 2, 2009; Published January 6, 2010 Copyright: ß 2010 Crawford et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported in part by awards from the Department of Defense Breast Cancer Research Program (BC050389) to Dr. Anatasha Crawford, and from the U.S. Department of Health and Human Services (R01-CA131465) and Department of Defense (BC073977) to Dr. R. Clarke. Flow Cytometry, Microscopy and Imaging, and Tissue Culture Shared Resources are supported by P30-CA-51008-16. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]. Introduction membrane depolarization and caspase activation [6]. BCL-W acts by binding to pro-apoptotic BCL2 family members and Approximately 70% of all newly diagnosed breast cancers preventing mitochondria-mediated apoptosis [7]. Overexpression express estrogen receptor-alpha (ER) [1], many of which are of BCL-W can prevent cell death [6] but its role(s) in affecting sensitive to antiestrogens. The steroidal antiestrogen ICI 182,780 breast cancer cell fate decisions or antiestrogen responsiveness is (ICI; Faslodex, Fulvestrant) is a selective ER downregulator unknown. BCL2 also blocks the induction of apoptosis by (SERD) that acts as an ER antagonist and enhances ubiquitin- inhibiting the activation of pro-apoptotic family members such mediated ER degradation. ICI is an effective second-line as BAX and preventing mitochondrial membrane depolarization treatment for TAM resistant, ER-positive (ER+) tumors, and is [8,9]. Overexpression of BCL2 is a potential mediator of resistance as effective as some aromatase inhibitors [2,3]. One limitation of to several chemotherapeutic drugs [10]. antiestrogen therapy is the prevalence of de novo and acquired BCL2 family members also play essential roles in autophagy resistance in breast cancer. Acquired antiestrogen resistance (macroautophagy), a process characterized by the presence of occurs when a tumor has an initially beneficial response to autophagosomes that engulf damaged organelles for subsequent antiestrogen treatment but the remaining tumor cells stop lysosomal degradation. Several anti-apoptotic BCL2 family mem- responding [4,5]. We report the roles of BCL2L2 (BCL-W), bers inhibit the activity of BECN1 [11], a key regulator of BCL2, and Beclin-1 (BECN1) in affecting responsiveness to ICI- autophagy [12] that binds to PIK3C3 to facilitate autophagosome resistance, and describe how anti-apoptotic BCL2 family members production [13]. However, the precise relationships between are involved in determining breast cancer cell fate. apoptosis and autophagy are unclear. Apoptosis or autophagy can BCL2 family proteins are essential regulators of apoptosis. each lead to cell death, but in some cellular contexts autophagy is a BCL2 and BCL-W are both antiapoptotic members of this family. pro-survival process, for example, in the face of nutrient deprivation BCL-W maintains cell viability by preventing mitochondrial [11]. While autophagy can contribute to TAM resistance in some PLoS ONE | www.plosone.org 1 January 2010 | Volume 5 | Issue 1 | e8604 BCL2, BCL-W, and AE Resistance breast cancer cells [14–16], its role in response to other and BCL2 improves ICI sensitivity in antiestrogen-sensitive cells antiestrogens is unknown. In ER+ MCF-7 breast cancer cells by increasing apoptosis. Therefore, BCL-W, BCL2, and BECN1 treated with camptothecin, autophagy prolongs survival and delays integrate central functions in determining ICI responsiveness likely apoptosis [17]. In marked contrast, autophagy promotes apoptosis by regulating functional autophagy to dictate the balance between in MCF-7 cells treated with the cytotoxic diterpenoid oridonin, apoptotic and necrotic cell death. where an inhibition of autophagy increases cell survival [18]. We determined whether BCL-W and BCL2 regulate ICI Results response in human breast cancer cells, and whether any effects involve changes in apoptosis and/or BECN1-associated autoph- We measured endogenous BCL-W and BCL2 expression in agy. We used three estrogen-independent cell lines: MCF-7/ control and ICI treated resistant and sensitive cells. BCL2 expression LCC1 (ICI sensitive) [19], and LY2 and MCF-7/LCC9 cells that was significantly higher in ethanol control and ICI treated (resistant) are crossresistant to TAM and ICI [20,21]. We show that co- MCF-7/LCC9 cells when compared to (sensitive) MCF-7/LCC1 inhibition of BCL-W and BCL2 restores sensitivity to the growth- cells (Figure 1A; ANOVA p = 0.002). BCL-W expression was lower inhibitory effects of ICI in both MCF-7/LCC9 and LY2 cells. In in MCF-7/LCC1 cells after 24 hr of ICI treatment and increased in re-sensitized cells, ICI treatment increases the levels of autophagy both sensitive and resistant cells after 72 hr of ICI treatment. and necrosis but has no effect on apoptosis. Inhibition of However, the levels in resistant cells remained higher than in autophagy by 3-methyladenine (3MA) or BECN1 shRNA under sensitive cells (Figure 1B; ANOVA p = 0.004;). these conditions reduces necrosis and increases apoptosis. Thus, To determine if BCL2 transcription is regulated in antiestrogen- restoration of ICI sensitivity with BCL-W+BCL2 inhibition resistant cells, we measured basal BCL2 promoter activity using a appears to occur through increasing an autophagy-associated BCL2-luciferase promoter-reporter assay. Basal BCL2 promoter necrotic cell death. Finally, we show that co-inhibiting BCL-W activity was increased 14-fold in MCF-7/LCC9 cells (Figure S1; Figure 1. Increased expression of BCL-W and BCL2 in MCF-7/LCC9 cells. Whole cell lysates were subjected to Western blot analysis with a specific BCL2 or BCL-W antibody. (A) Bars represent the mean6SE of the relative BCL2:actin ratio (normalized to control cells) for three independent experiments. Inset, a representative blot.(B) Bars represent the mean6SE of the relative BCL-W:actin ratio (normalized to control cells) for three independent experiments. Inset, a representative blot. doi:10.1371/journal.pone.0008604.g001 PLoS ONE | www.plosone.org 2 January 2010 | Volume 5 | Issue 1 | e8604 BCL2, BCL-W, and AE Resistance p,0.003) when compared to MCF-7/LCC1 cells, suggesting that Total cell number was significantly decreased after treatment with the transcriptional regulation of basal BCL2 expression is altered both concentrations of ICI and/or YC137 in MCF-7/LCC1 cells in MCF-7/LCC9 cells. (ANOVA p,0.001; Fig. 2A). RI = 2.56 (20 nmol/L ICI)
Load more

Recommended publications
  • Autophagy Patterns and Prognosis in Uveal Melanomas
    Modern Pathology (2011) 24, 1036–1045 1036 & 2011 USCAP, Inc. All rights reserved 0893-3952/11 $32.00 Autophagy patterns and prognosis in uveal melanomas Alexandra N Giatromanolaki1, Georgios St Charitoudis2, Nikolaos E Bechrakis3, Vassilios P Kozobolis4, Michael I Koukourakis5, Michael H Foerster2 and Efthimios L Sivridis1 1Department of Pathology, Democritus University of Thrace Medical School, Alexandroupolis, Greece; 2Department of Ophthalmology, Charite´ Medical University, Campus Benjamin Franklin, Berlin, Germany; 3Department of Ophthalmology, University of Innsbruck Medical School, Innsbruck, Austria; 4Department of Ophthalmology, Democritus University of Thrace Medical School, Alexandroupolis, Greece and 5Department of Radiotherapy/Oncology, Democritus University of Thrace Medical School, Alexandroupolis, Greece Autophagy is a self-degradation mechanism by which cells recycle their own cytoplasmic constituents. It has been claimed that, under certain conditions, such a process may be associated with tumor progression. In this study, the autophagic activity was investigated in a series of 99 uveal melanomas after immunohistochemical staining for the autophagy-associated proteins MAP1LC3A and BECN1, most commonly known as LC3A and Beclin 1, respectively. These were assessed in parallel with the hypoxia-inducible factor 1a (HIF1A) and its downstream protein lactate dehydrogenase 5 (composed by five LDHA subunits). Increased autophagic reactivity, detected by MAP1LC3A or BECN1, was associated with intense pigmentation and tumor hypoxia. Uveal melanomas with extensive overexpression of BECN1 or those with underexpression of this protein were associated with the worst prognosis, but the former manifested metastases much earlier than the latter; only 58% of patients with extensive BECN1 overexpression were alive at 4 years, compared with 80% of patients with underexpressed patterns.
    [Show full text]
  • Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration
    The Journal of Neuroscience, March 20, 2013 • 33(12):5195–5207 • 5195 Neurobiology of Disease Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration Katharina E. Cosker,1,2,3 Maria F. Pazyra-Murphy,1,2,3 Sara J. Fenstermacher,1,2,3 and Rosalind A. Segal1,2,3 1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and Departments of 2Cancer Biology and 3Pediatric Oncology, Dana- Farber Cancer Institute, Boston, Massachusetts 02215 Establishment of neuronal circuitry depends on both formation and refinement of neural connections. During this process, target- derived neurotrophins regulate both transcription and translation to enable selective axon survival or elimination. However, it is not known whether retrograde signaling pathways that control transcription are coordinated with neurotrophin-regulated actions that transpire in the axon. Here we report that target-derived neurotrophins coordinate transcription of the antiapoptotic gene bclw with transport of bclw mRNA to the axon, and thereby prevent axonal degeneration in rat and mouse sensory neurons. We show that neurotrophin stimulation of nerve terminals elicits new bclw transcripts that are immediately transported to the axons and translated into protein. Bclw interacts with Bax and suppresses the caspase6 apoptotic cascade that fosters axonal degeneration. The scope of bclw regulation at the levels of transcription, transport, and translation provides a mechanism whereby sustained neurotrophin stimulation
    [Show full text]
  • Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain
    biomolecules Article Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain Arvind Ramanathan 1,2,*, Akash Parvatikar 3, Srinivas C. Chennubhotla 3,* and Yang Mei 4,† and Sangita C. Sinha 4,* 1 Data Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA 2 Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL 60637, USA 3 Department of Computational and Systems Biology, University of Pittsburgh, PA 15260, USA; [email protected] 4 Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, USA; [email protected] * Correspondence: [email protected] (A.R.); [email protected] (S.C.C.); [email protected] (S.C.S.); Tel.: +1-630-252-3805 (A.R.); +1-412-648-7794 (S.C.C.); +1-701-231-5658 (S.C.S.) † Current address: The Wistar Institute, Philadelphia, PA 19104, USA. Received: 27 July 2020; Accepted: 4 September 2020; Published: 11 September 2020 Abstract: Viral BCL2 proteins (vBCL2s) help to sustain chronic infection of host proteins to inhibit apoptosis and autophagy. However, details of conformational changes in vBCL2s that enable binding to BH3Ds remain unknown. Using all-atom, multiple microsecond-long molecular dynamic simulations (totaling 17 µs) of the murine g-herpesvirus 68 vBCL2 (M11), and statistical inference techniques, we show that regions of M11 transiently unfold and refold upon binding of the BH3D. Further, we show that this partial unfolding/refolding within M11 is mediated by a network of hydrophobic interactions, which includes residues that are 10 Å away from the BH3D binding cleft.
    [Show full text]
  • Mitophagy Confers Resistance to Siderophore-Mediated Killing by Pseudomonas Aeruginosa
    Mitophagy confers resistance to siderophore-mediated killing by Pseudomonas aeruginosa Natalia V. Kirienkoa,b, Frederick M. Ausubela,b,1, and Gary Ruvkuna,b,1,2 aDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; and bDepartment of Genetics, Harvard Medical School, Boston, MA 02115 Contributed by Gary Ruvkun, December 31, 2014 (sent for review December 19, 2014) In the arms race of bacterial pathogenesis, bacteria produce an Results and Discussion array of toxins and virulence factors that disrupt core host Pyoverdin Enters C. elegans and Is Sufficient to Mediate Host Killing. processes. Hosts mitigate the ensuing damage by responding with Despite the presence of rich sources of iron within host cells, immune countermeasures. The iron-binding siderophore pyover- siderophores are generally assumed to scavenge iron from fer- din is a key virulence mediator of the human pathogen Pseudo- riproteins present in the extracellular milieu. However, we hy- monas aeruginosa, but its pathogenic mechanism has not been pothesize that siderophores are capable of harvesting iron from established. Here we demonstrate that pyoverdin enters Caen- intracellular sources and, consequently, function directly as orhabditis elegans and that it is sufficient to mediate host killing. toxins. We exposed worms to a pyoverdin-enriched, cell-free Moreover, we show that iron chelation disrupts mitochondrial ho- bacterial growth media for 24 h to determine whether detectable meostasis and triggers mitophagy both in C. elegans and mamma- levels of pyoverdin could be identified within the host. After lian cells. Finally, we show that mitophagy provides protection exposure, worms were washed extensively, homogenized, and both against the extracellular pathogen P.
    [Show full text]
  • Supplementary Table 2
    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942
    [Show full text]
  • Phenotype-Based Drug Screening Reveals Association Between Venetoclax Response and Differentiation Stage in Acute Myeloid Leukemia
    Acute Myeloid Leukemia SUPPLEMENTARY APPENDIX Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia Heikki Kuusanmäki, 1,2 Aino-Maija Leppä, 1 Petri Pölönen, 3 Mika Kontro, 2 Olli Dufva, 2 Debashish Deb, 1 Bhagwan Yadav, 2 Oscar Brück, 2 Ashwini Kumar, 1 Hele Everaus, 4 Bjørn T. Gjertsen, 5 Merja Heinäniemi, 3 Kimmo Porkka, 2 Satu Mustjoki 2,6 and Caroline A. Heckman 1 1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki; 2Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki; 3Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; 4Department of Hematology and Oncology, University of Tartu, Tartu, Estonia; 5Centre for Cancer Biomarkers, De - partment of Clinical Science, University of Bergen, Bergen, Norway and 6Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland ©2020 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2018.214882 Received: December 17, 2018. Accepted: July 8, 2019. Pre-published: July 11, 2019. Correspondence: CAROLINE A. HECKMAN - [email protected] HEIKKI KUUSANMÄKI - [email protected] Supplemental Material Phenotype-based drug screening reveals an association between venetoclax response and differentiation stage in acute myeloid leukemia Authors: Heikki Kuusanmäki1, 2, Aino-Maija
    [Show full text]
  • BCL2L2 (NM 004050) Human Tagged ORF Clone – RC211152 | Origene
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC211152 BCL2L2 (NM_004050) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: BCL2L2 (NM_004050) Human Tagged ORF Clone Tag: Myc-DDK Symbol: BCL2L2 Synonyms: BCL-W; BCL2-L-2; BCLW; PPP1R51 Vector: pCMV6-Entry (PS100001) E. coli Selection: Kanamycin (25 ug/mL) Cell Selection: Neomycin ORF Nucleotide >RC211152 ORF sequence Sequence: Red=Cloning site Blue=ORF Green=Tags(s) TTTTGTAATACGACTCACTATAGGGCGGCCGGGAATTCGTCGACTGGATCCGGTACCGAGGAGATCTGCC GCCGCGATCGCC ATGGCGACCCCAGCCTCGGCCCCAGACACACGGGCTCTGGTGGCAGACTTTGTAGGTTATAAGCTGAGGC AGAAGGGTTATGTCTGTGGAGCTGGCCCCGGGGAGGGCCCAGCAGCTGACCCGCTGCACCAAGCCATGCG GGCAGCTGGAGATGAGTTCGAGACCCGCTTCCGGCGCACCTTCTCTGATCTGGCGGCTCAGCTGCATGTG ACCCCAGGCTCAGCCCAACAACGCTTCACCCAGGTCTCCGATGAACTTTTTCAAGGGGGCCCCAACTGGG GCCGCCTTGTAGCCTTCTTTGTCTTTGGGGCTGCACTGTGTGCTGAGAGTGTCAACAAGGAGATGGAACC ACTGGTGGGACAAGTGCAGGAGTGGATGGTGGCCTACCTGGAGACGCGGCTGGCTGACTGGATCCACAGC AGTGGGGGCTGGGCGGAGTTCACAGCTCTATACGGGGACGGGGCCCTGGAGGAGGCGCGGCGTCTGCGGG AGGGGAACTGGGCATCAGTGAGGACAGTGCTGACGGGGGCCGTGGCACTGGGGGCCCTGGTAACTGTAGG GGCCTTTTTTGCTAGCAAG ACGCGTACGCGGCCGCTCGAGCAGAAACTCATCTCAGAAGAGGATCTGGCAGCAAATGATATCCTGGATT ACAAGGATGACGACGATAAGGTTTAA Protein Sequence: >RC211152 protein sequence Red=Cloning site Green=Tags(s) MATPASAPDTRALVADFVGYKLRQKGYVCGAGPGEGPAADPLHQAMRAAGDEFETRFRRTFSDLAAQLHV TPGSAQQRFTQVSDELFQGGPNWGRLVAFFVFGAALCAESVNKEMEPLVGQVQEWMVAYLETRLADWIHS
    [Show full text]
  • Alterations of the Interactome of Bcl-2 Proteins in Breast Cancer at the Transcriptional, Mutational and Structural Level
    RESEARCH ARTICLE Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level Simon Mathis Kønig1, Vendela Rissler1, Thilde Terkelsen1, Matteo Lambrughi1, 1,2 Elena PapaleoID * 1 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark, a1111111111 2 Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark a1111111111 a1111111111 * [email protected] a1111111111 a1111111111 Abstract Apoptosis is an essential defensive mechanism against tumorigenesis. Proteins of the B- OPEN ACCESS cell lymphoma-2 (Bcl-2) family regulate programmed cell death by the mitochondrial apopto- sis pathway. In response to intracellular stress, the apoptotic balance is governed by inter- Citation: Kønig SM, Rissler V, Terkelsen T, Lambrughi M, Papaleo E (2019) Alterations of the actions of three distinct subgroups of proteins; the activator/sensitizer BH3 (Bcl-2 homology interactome of Bcl-2 proteins in breast cancer at 3)-only proteins, the pro-survival, and the pro-apoptotic executioner proteins. Changes in the transcriptional, mutational and structural level. expression levels, stability, and functional impairment of pro-survival proteins can lead to an PLoS Comput Biol 15(12): e1007485. https://doi. imbalance in tissue homeostasis. Their overexpression or hyperactivation can result in org/10.1371/journal.pcbi.1007485 oncogenic effects. Pro-survival Bcl-2 family members carry out their function by binding the Editor: Igor N. Berezovsky, A�STAR Singapore, BH3 short linear motif of pro-apoptotic proteins in a modular way, creating a complex net- SINGAPORE work of protein-protein interactions. Their dysfunction enables cancer cells to evade cell Received: July 8, 2019 death.
    [Show full text]
  • A 40-Cm Region on Chromosome 14 Plays a Critical Role in the Development of Virus Persistence, Demyelination, Brain Pathology An
    A 40-cM Region on Chromosome 14 Plays a Critical Role in the Development of Virus Persistence, Demyelination, Brain Pathology and Neurologic Deficits in a Murine Viral Model of Multiple Sclerosis Shunya Nakane, Laurie Zoecklein, Jeffrey Gamez, Louisa Papke, Kevin Pavelko, Jean- François Bureau, Michel Brahic, Larry Pease, Moses Rodriguez To cite this version: Shunya Nakane, Laurie Zoecklein, Jeffrey Gamez, Louisa Papke, Kevin Pavelko, et al.. A 40-cM Region on Chromosome 14 Plays a Critical Role in the Development of Virus Persistence, Demyelination, Brain Pathology and Neurologic Deficits in a Murine Viral Model of Multiple Sclerosis. Brain Pathology, Wiley, 2003, 13 (4), pp.519-533. 10.1111/j.1750-3639.2003.tb00482.x. hal-03223233 HAL Id: hal-03223233 https://hal.archives-ouvertes.fr/hal-03223233 Submitted on 10 May 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. RESEARCH ARTICLE A 40-cM Region on Chromosome 14 Plays a Critical Role in the Development of Virus Persistence, Demyelination, Brain Pathology and Neurologic Deficits in a Murine Viral Model of Multiple Sclerosis Shunya Nakane1; Laurie J. Zoecklein1; Jeffrey D. Introduction Gamez1; Louisa M. Papke1; Kevin D.
    [Show full text]
  • Molecular and Genetic Analysis of Parkin in Microglial Activation and Inflammation-Related Neurodegeneration
    MOLECULAR AND GENETIC ANALYSIS OF PARKIN IN MICROGLIAL ACTIVATION AND INFLAMMATION-RELATED NEURODEGENERATION APPROVED BY SUPERVISORY COMMITTEE Malú Tansey, Ph.D. Matthew S. Goldberg, Ph.D. Zhijian Chen, Ph.D. David Farrar, Ph.D. Gang Yu, Ph.D. DEDICATION This is dedicated to my family for their love and support and to my husband (to be) Andy. MOLECULAR AND GENETIC ANALYSIS OF PARKIN IN MICROGLIAL ACTIVATION AND INFLAMMATION-RELATED NEURODEGENERATION by THI ANH TRAN DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas March, 2010 Copyright by THI ANH TRAN, 2010 All Rights Reserved MOLECULAR AND GENETIC ANALYSIS OF PARKIN IN MICROGLIAL ACTIVATION AND INFLAMMATION-RELATED NEURODEGENERATION THI ANH TRAN The University of Texas Southwestern Medical Center at Dallas, 2010 MALU TANSEY, Ph.D. Parkinson’s disease (PD) is a progressive, neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Genetic mutations account for only 5-10% of PD cases. Oxidative stress and inflammation have both been linked to sporadic PD. Inflammation-induced injury to dopaminergic neurons can be significantly attenuated by impairment of microglial activation. In addition, previous studies from our lab reported that parkin-/- mice are more susceptible to inflammation- induced degeneration of nigral DA neurons. Therefore, inflammatory responses are a critical determinant of DA neuronal survival. v Microglia support neuronal survival by providing trophic factors and phagocytosing debris.
    [Show full text]
  • Biology of the Caenorhabditis Elegans Germline Stem Cell System
    | WORMBOOK CELL FATE, SIGNALING, AND DEVELOPMENT Biology of the Caenorhabditis elegans Germline Stem Cell System E. Jane Albert Hubbard*,1 and Tim Schedl†,1 *Skirball Institute of Biomolecular Medicine, Departments of Cell Biology and Pathology, New York University School of Medicine, † New York 10016 and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110 ORCID IDs: 0000-0001-5893-7232 (E.J.A.H.); 0000-0003-2148-2996 (T.S.) ABSTRACT Stem cell systems regulate tissue development and maintenance. The germline stem cell system is essential for animal reproduction, controlling both the timing and number of progeny through its influence on gamete production. In this review, we first draw general comparisons to stem cell systems in other organisms, and then present our current understanding of the germline stem cell system in Caenorhabditis elegans. In contrast to stereotypic somatic development and cell number stasis of adult somatic cells in C. elegans, the germline stem cell system has a variable division pattern, and the system differs between larval development, early adult peak reproduction and age-related decline. We discuss the cell and developmental biology of the stem cell system and the Notch regulated genetic network that controls the key decision between the stem cell fate and meiotic development, as it occurs under optimal laboratory conditions in adult and larval stages. We then discuss alterations of the stem cell system in response to environ- mental perturbations and aging. A recurring distinction is between processes that control stem cell fate and those that control cell cycle regulation. C. elegans is a powerful model for understanding germline stem cells and stem cell biology.
    [Show full text]
  • Beclin-1 Expression Is Retained in High-Grade Serous Ovarian Cancer Yet Is Not Essential for Autophagy Induction in Vitro Rohann J
    Western University Scholarship@Western Biochemistry Publications Biochemistry Department 8-2015 Beclin-1 Expression is Retained in High-Grade Serous Ovarian Cancer yet is Not Essential for Autophagy Induction In Vitro Rohann J. M. Correa Western University Yudith Ramos Valdes London Regional Cancer Program Trevor G. Shepherd Western University Gabriel E. DiMattia Western University, [email protected] Follow this and additional works at: https://ir.lib.uwo.ca/biochempub Part of the Biochemistry Commons Citation of this paper: Correa, Rohann J. M.; Valdes, Yudith Ramos; Shepherd, Trevor G.; and DiMattia, Gabriel E., "Beclin-1 Expression is Retained in High- Grade Serous Ovarian Cancer yet is Not Essential for Autophagy Induction In Vitro" (2015). Biochemistry Publications. 166. https://ir.lib.uwo.ca/biochempub/166 Correa et al. Journal of Ovarian Research (2015) 8:52 DOI 10.1186/s13048-015-0182-y RESEARCH Open Access Beclin-1 expression is retained in high-grade serous ovarian cancer yet is not essential for autophagy induction in vitro Rohann J. M. Correa1,2, Yudith Ramos Valdes1, Trevor G. Shepherd1,3,4,5† and Gabriel E. DiMattia1,2,3,4,6*† Abstract Background: Autophagy is a conserved cellular self-digestion mechanism that can either suppress or promote cancer in a context-dependent manner. In ovarian cancer, prevalent mono-allelic deletion of BECN1 (a canonical autophagy-inducer) suggests that autophagy is impaired to promote carcinogenesis and that Beclin-1 is a haploinsufficient tumor suppressor. Nonetheless, autophagy is known to be readily inducible in ovarian cancer cells. We sought to clarify whether Beclin-1 expression is in fact disrupted in ovarian cancer and whether this impacts autophagy regulation.
    [Show full text]