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1. Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations

Author

Mollereau, B., Rzechorzek, N. M., Roussel, B. D., Sedru, M., Brink, D., Bailly-Maitre, B., Palladino, F., Medinas, D. B., Domingos, P. M., Hunot, S., Chandran, S., Birman, S., Baron, T., Vivien, D., Duarte, C. B., Ryoo, H. D., Steller, H., Urano, F., Chevet, E., Kroemer, G., Ciechanover, A., Calabrese, E. J., Kaufman, R. J., Hetz, C, Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, Oncogenesis Stress Signaling ( OSS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CRLCC Eugène Marquis ( CRLCC ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Rockefeller University [New York], Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), USA2013-0003, Comisión Nacional de Investigación Científica y Tecnológica, 382453, Muscular Dystrophy Association, IRE1-PD ANR-13-ISV4-0003-01, ANR/FCT, ANR-10-LABX-54 MEMOLIFE, Labex MemoLife, Dr. Miriam and Sheldon Adelson Medical Research Foundation (AMRF), 1775/12, Israel Centers of Research Excellence Program, 096409/Z/11/Z, Wellcome Trust Integrated Training Fellowship for Veterinarians, P09-015-F, Millennium Institute, 15150012, FONDAP, 2014-F-059, Frick Foundation, ALS Therapy Alliance, C13S02, COPEC-UC Foundation, N62909-16-1-2003, Office of Naval Research-Global (ONR-G), R01 EY020866, National Institutes of Health, AL150111, CDMRP Amyotrophic Lateral Sclerosis Research, Program (ALSRP) Therapeutic Idea Award, 2012-00034435, Fondation de France, FCT-ANR/NEU-NMC/0006/2013, Fundação para a Ciência e a Tecnologia, Israel Cancer Research Fund, 1-12-CT-61, American Diabetes Association, 3150113, Fondo Nacional de Desarrollo Científico y Tecnológico, Israel Science Foundation, 17-2013-512, Juvenile Diabetes Research Foundation International, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)

Subjects
ATF4, activating transcription factor 4, [SDV]Life Sciences [q-bio], S1P, site 1 protease, UPR, unfolded protein response, xCT, cystine/glutamate antiporter, Ischemia, eIF2α, eukaryotic translation initiation factor 2α, Bim, Bcl-2-interacting mediator of cell death, Parkinson, ARE, anti-oxidant response element, Ub, ubiquitin, HO-1, heme oxygenase-1, 6-OHDA, 6-hydroxydopamine, ATF6α, activating transcription factor 6α, Hsp70, heat shock protein 70, DA, dopaminergic, Endoplasmic Reticulum Stress, LRRK2, leucine-rich repeat kinase 2, SNpc, substantia nigra pars compacta, OGD, oxygen and glucose deprivation, MPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, ASK1, apoptosis signal regulating kinase 1, BDNF, brain-derived neurotrophic factor, MANF, mesencephalic astrocyte-derived neurotrophic factor, PMD, protein misfolding disorder, SERCA, sarcoplasmic-ER Mg2+/Ca2+ ATPase, ER stress, Signal Transduction, BI-1, Bax-inhibitor-1, iPSC, induced pluripotent stem cell, Proteasome Endopeptidase Complex, Neuroscience(all), Clinical Neurology, IRE1, inositol-requiring enzyme 1, nAChRs, nicotinic acetylcholine receptors, Article, XBP1, x-box binding protein 1, ER, endoplasmic reticulum, GEF, guanine nucleotide exchange factor, ROS, reactive oxygen species, UPS, ubiquitin proteasome system, Hormesis, ERAD, ER-associated protein degradation, SOD, superoxide dismutase, Autophagy, BiP/GRP78, binding immunoglobulin protein, Animals, Humans, Proteostasis Deficiencies, JNK, Jun amino terminal kinase, MCAO, middle cerebral artery occlusion, Molecular Biology, CHOP, C/EBP-homologous protein, PD, Parkinson’s disease, S2P, site 2 protease, PUMA, p53 upregulated modulator of apoptosis, Wolfram syndrome, [ SDV ] Life Sciences [q-bio], Proteasome, Ubiquitin, HIF-1, hypoxia-inducible transcription factor-1, RBM3, RNA binding motif 3, Wfs1, wolframin, PHD, prolyl-hydroxylases, CIRBP, cold-inducible RNA binding protein, tPA, tissue plasminogen activator, EGFR, epidermal growth factor receptor, HD, Huntington’s disease, CDNF, cerebral dopamine neurotrophic factor, PERK, protein kinase RNA-like ER kinase, Parkinson׳s disease, RIDD, regulated IRE1-dependent decay, Unfolded Protein Response, IRI, ischemia reperfusion injury, GADD34, growth arrest and DNA damage–inducible 34, NF-KB, nuclear factor-kappa B, Nervous System Diseases, Glioblastoma, 3-MA, 3-methyladenine, Developmental Biology
Abstract

In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress., Highlights • The proteostasis network is perturbed in neurological diseases. • UPR, UPS and autophagy are adaptive responses to maintain cell function. • Adaptive responses induced by preconditioning could be used for therapeutics.

Published
2016
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2. Selective Catalytic Electroreduction of CO2 at Silicon Nanowires (SiNWs) Photocathodes Using Non-Noble Metal-Based Manganese Carbonyl Bipyridyl Molecular Catalysts in Solution and Grafted onto SiNWs

Author

Mollereau, B., Rzechorzek, N. M., Roussel, B. D., Sedru, M., Brink, D., Bailly-Maitre, B., Palladino, F., Medinas, D. B., Domingos, P. M., Hunot, S., Chandran, S., Birman, S., Baron, T., Vivien, D., Duarte, C. B., Ryoo, H. D., Steller, H., Urano, F., Chevet, E., Kroemer, G., Ciechanover, A., Calabrese, E. J., Kaufman, R. J., Hetz, C, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Département de Chimie Moléculaire (DCM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Joseph Fourier - Grenoble 1 (UJF), ANR-11-LABX-0003-01, Agence Nationale de la Recherche, Institut de Chimie Moléculaire de Grenoble, ANR-11-LABX-0003,ARCANE,Grenoble, une chimie bio-motivée(2011), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Laboratory of Apoptosis and Cancer Biology, Rockefeller University [New York], Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Photocurrent, Materials science, Silicon, 010405 organic chemistry, Inorganic chemistry, chemistry.chemical_element, General Chemistry, Manganese, Glassy carbon, 010402 general chemistry, 01 natural sciences, 7. Clean energy, Catalysis, 0104 chemical sciences, chemistry, Electrode, [CHIM]Chemical Sciences, Cyclic voltammetry, Silicon nanowires
Abstract

International audience; The electrocatalytic redn. of CO2 to CO in hydroorg. medium has been investigated at illuminated (λ \textgreater 600 nm; 20 mW cm-2) hydrogen-terminated silicon nanowires (SiNWs-H) photocathodes using three Mn-based carbonyl bipyridyl complexes as homogeneous mol. catalysts ([Mn(L) (CO)3(CH3CN)](PF6) and [Mn(bpy) (CO)3Br] with L = bpy = 2,2'-bipyridine and dmbpy = 4,4'-dimethyl-2,2'-bipyridine). Systematic comparison of their cyclic voltammetry characteristics with those obtained at flat hydrogen-terminated silicon and traditional glassy carbon electrodes (GCE) enabled us to demonstrate the superior catalytic efficiency of SiNWs-H in terms of cathodic photocurrent densities and overpotentials. For example, the photocurrent densities measured at -1.0 V vs SCE for [Mn(bpy) (CO)3(CH3CN)](PF6) at SiNWs-H exceeded 1.0 mA cm-2 in CO2-satd. CH3CN + 5% vol./vol. H2O, whereas almost zero current was measured at this potential at GCE. Such characteristics have been supported by the energetic diagrams built for the different SiNWs\textbarMn-based catalyst interfaces. The fill factor FF and energy conversion efficiency η calcd. under catalytic conditions were higher for [Mn(bpy or dmbpy) (CO)3(CH3CN)](PF6) (FF = 0.35 and 0.34; η = 3.0 and 2.0%, resp.). Further preparative-scale electrolysis at SiNWs-H photocathode with Mn-based complex catalysts in electrolytic soln. evidenced the quant. conversion of CO2 to CO with a higher stability of the [Mn(dmbpy) (CO)3(CH3CN)](PF6) complex. Finally, in order to develop technol. viable electrocatalytic devices, the elaboration of SiNWs-H photoelectrodes modified with a Mn-based complex has been successfully achieved from an electropolymerizable catalyst, and it was shown that the electrocatalytic activity of the complex was retained after immobilization.

Published
2015
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11. Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation.

Author

Dichtel-Danjoy, M-L, Ma, D, Dourlen, P, Chatelain, G, Napoletano, F, Robin, M, Corbet, M, Levet, C, Hafsi, H, Hainaut, P, Ryoo, H D, Bourdon, J-C, and Mollereau, B

Subjects
DROSOPHILA, APOPTOSIS, CELL proliferation, AUTOPHAGY, ADAPTOR proteins, DISEASE risk factors
Abstract

Irradiated or injured cells enter apoptosis, and in turn, promote proliferation of surrounding unaffected cells. In Drosophila, apoptotic cells have an active role in proliferation, where the caspase Dronc and p53 induce mitogen expression and growth in the surrounding tissues. The Drosophila p53 gene structure is conserved and encodes at least two protein isoforms: a full-length isoform (Dp53) and an N-terminally truncated isoform (DΔNp53). Historically, DΔNp53 was the first p53 isoform identified and was thought to be responsible for all p53 biological activities. It was shown that DΔNp53 induces apoptosis by inducing the expression of IAP antagonists, such as Reaper. Here we investigated the roles of Dp53 and DΔNp53 in apoptosis and apoptosis-induced proliferation. We found that both isoforms were capable of activating apoptosis, but that they each induced distinct IAP antagonists. Expression of DΔNp53 induced Wingless (Wg) expression and enhanced proliferation in both 'undead cells' and in 'genuine' apoptotic cells. In contrast to DΔNp53, Dp53 did not induce Wg expression in the absence of the endogenous p53 gene. Thus, we propose that DΔNp53 is the main isoform that regulates apoptosis-induced proliferation. Understanding the roles of Drosophila p53 isoforms in apoptosis and in apoptosis-induced proliferation may shed new light on the roles of p53 isoforms in humans, with important implications in cancer biology. [ABSTRACT FROM AUTHOR]

Published
2013
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12. Drosophila BRUCE inhibits apoptosis through non-lysine ubiquitination of the IAP-antagonist REAPER.

Author

Domingues, C and Ryoo, H D

Subjects
*DROSOPHILA, *APOPTOSIS, *CELLS, *GENE expression, *UBIQUITIN, *ENZYMES
Abstract

Active caspases execute apoptosis to eliminate superfluous or harmful cells in animals. In Drosophila, living cells prevent uncontrolled caspase activation through an inhibitor of apoptosis protein (IAP) family member, dIAP1, and apoptosis is preceded by the expression of IAP-antagonists, such as Reaper, Hid and Grim. Strong genetic modifiers of this pathway include another IAP family gene encoding an E2 ubiquitin conjugating enzyme domain, dBruce. Although the genetic effects of dBruce mutants are well documented, molecular targets of its encoded protein have remained elusive. Here, we report that dBruce targets Reaper for ubiquitination through an unconventional mechanism. Specifically, we show that dBruce physically interacts with Reaper, dependent upon Reaper's IAP-binding (IBM) and GH3 motifs. Consistently, Reaper levels were elevated in a dBruce −/− background. Unexpectedly, we found that dBruce also affects the levels of a mutant form of Reaper without any internal lysine residues, which normally serve as conventional ubiquitin acceptor sites. Furthermore, we were able to biochemically detect ubiquitin conjugation on lysine-deficient Reaper proteins, and knockdown of dBruce significantly reduced the extent of this ubiquitination. Our results indicate that dBruce inhibits apoptosis by promoting IAP-antagonist ubiquitination on unconventional acceptor sites. [ABSTRACT FROM AUTHOR]

Published
2012
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13. Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways.

Author

Herman-Bachinsky, Y., Ryoo, H.-D., Ciechanover, A., and Gonen, H.

Subjects
*LIGASES, *UBIQUITIN, *CELL death, *APOPTOSIS, *CELLULAR pathology
Abstract

Inhibitors of apoptosis proteins (IAPs) suppress cell death by inactivating proapoptotic regulators, and therefore play important roles in controlling apoptosis in normal and malignant cells. Many IAPs are ubiquitin ligases, and their activity is mediated via ubiquitination and subsequent degradation of their targets. Here we corroborate a previous observation that DIAP1 (Drosophila IAP1) can be degraded via a two-step mechanism: (i) limited caspase-mediated cleavage and (ii) degradation of the released fragment via the ubiquitin N-end rule pathway. Yet, we demonstrate that this pathway is not the only one involved in DIAP1 degradation, and the intact protein can be degraded independent of prior caspase cleavage. Importantly, this mode of degradation does not require the RING-finger-mediated autoubiquitinating activity of DIAP1, believed to target many RING-finger E3s for self-destruction. Our preliminary data suggest that DIAP2 mediates DIAP1 degradation, suggesting a novel regulatory loop within the apoptotic pathway. Studying the role of the autoubiquitinating activity of DIAP1, we demonstrate that it does not involve formation of Lys48-based polyubiquitin chains, but probably chains linked via Lys63. Our preliminary data suggest that the autoubiquitination serves to attenuate the ligase activity of DIAP1 towards its exogenous substrates.Cell Death and Differentiation (2007) 14, 861–871. doi:10.1038/sj.cdd.4402079; published online 5 January 2007 [ABSTRACT FROM AUTHOR]

Published
2007
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14. Regulation of Hox target genes by a DNA bound Homothorax/Hox/Extradenticle complex.

Author

Ryoo, H D, Marty, T, Casares, F, Affolter, M, and Mann, R S

Abstract

To regulate their target genes, the Hox proteins of Drosophila often bind to DNA as heterodimers with the homeodomain protein Extradenticle (EXD). For EXD to bind DNA, it must be in the nucleus, and its nuclear localization requires a third homeodomain protein, Homothorax (HTH). Here we show that a conserved N-terminal domain of HTH directly binds to EXD in vitro, and is sufficient to induce the nuclear localization of EXD in vivo. However, mutating a key DNA binding residue in the HTH homeodomain abolishes many of its in vivo functions. HTH binds to DNA as part of a HTH/Hox/EXD trimeric complex, and we show that this complex is essential for the activation of a natural Hox target enhancer. Using a dominant negative form of HTH we provide evidence that similar complexes are important for several Hox- and exd-mediated functions in vivo. These data suggest that Hox proteins often function as part of a multiprotein complex, composed of HTH, Hox, and EXD proteins, bound to DNA.

Published
1999

15. Switching the in vivo specificity of a minimal Hox-responsive element.

Author

Chan, S K, Ryoo, H D, Gould, A, Krumlauf, R, and Mann, R S

Abstract

The homeodomain proteins encoded by the Hox complex genes do not bind DNA with high specificity. In vitro, Hox specificity can be increased by binding to DNA cooperatively with the homeodomain protein extradenticle or its vertebrate homologs, the pbx proteins (together, the PBC family). Here we show that a two basepair change in a Hox-PBC binding site switches the Hox-dependent expression pattern generated in vivo, from labial to Deformed. The change in vivo correlates with an altered Hox binding specificity in vitro. Further, we identify similar Deformed-PBC binding sites in the Deformed and Hoxb-4 genes and show that they generate Deformed or Hoxb-4 expression patterns in Drosophila and mouse embryos, respectively. These results suggest a model in which Hox-PBC binding sites play an instructive role in Hox specificity by promoting the formation of different Hox-PBC heterodimers in vivo. Thus, the choice of Hox partner, and therefore Hox target genes, depends on subtle differences between Hox-PBC binding sites.

Published
1997

16. Switching the in vivo specificity of a minimal Hox-responsive element

Author

Chan, S. -K, Ryoo, H. -D, Gould, A., Robb Krumlauf, and Mann, R. S.

Subjects
Homeodomain Proteins, animal structures, Binding Sites, Genes, Homeobox, Gene Expression Regulation, Developmental, Mice, Transgenic, DNA, digestive system diseases, Animals, Genetically Modified, DNA-Binding Proteins, Mice, embryonic structures, Mutation, Animals, Drosophila Proteins, Insect Proteins, Drosophila, skin and connective tissue diseases, Promoter Regions, Genetic, Molecular Biology, Dimerization, Developmental Biology, Repetitive Sequences, Nucleic Acid, Transcription Factors
Abstract

The homeodomain proteins encoded by the Hox complex genes do not bind DNA with high specificity. In vitro, Hox specificity can be increased by binding to DNA cooperatively with the homeodomain protein extradenticle or its vertebrate homologs, the pbx proteins (together, the PBC family). Here we show that a two basepair change in a Hox-PBC binding site switches the Hox-dependent expression pattern generated in vivo, from labial to Deformed. The change in vivo correlates with an altered Hox binding specificity in vitro. Further, we identify similar Deformed-PBC binding sites in the Deformed and Hoxb-4 genes and show that they generate Deformed or Hoxb-4 expression patterns in Drosophila and mouse embryos, respectively. These results suggest a model in which Hox-PBC binding sites play an instructive role in Hox specificity by promoting the formation of different Hox-PBC heterodimers in vivo. Thus, the choice of Hox partner, and therefore Hox target genes, depends on subtle differences between Hox-PBC binding sites.

18. Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation

Author

Hyung Don Ryoo, Clemence Levet, Pierre Hainaut, Francesco Napoletano, Marion Robin, M. Corbet, Jean-Christophe Bourdon, Bertrand Mollereau, Dali Ma, Marie-Laure Dichtel-Danjoy, Gilles Chatelain, Hind Hafsi, Pierre Dourlen, Dichtel-Danjoy, M. -L., Ma, D., Dourlen, P., Chatelain, G., Napoletano, F., Robin, M., Corbet, M., Levet, C., Hafsi, H., Hainaut, P., Ryoo, H. D., Bourdon, J. -C., Mollereau, B., Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Molecular Carcinogenesis Group, International Agency for Cancer Research (IACR), Sect Mech Carcinogenesis, Department of Cell Biology, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Division of Medical Sciences, University of Dundee-Centre for Oncology and Molecular Medicine, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
p53, Gene isoform, apoptosis, Drosophila, hid, reaper, regeneration, Animals, Animals, Genetically Modified, Apoptosis, Cell Growth Processes, Protein Isoforms, Signal Transduction, Tumor Suppressor Protein p53, Molecular Biology, Cell Biology, [SDV]Life Sciences [q-bio], Genetically Modified, Endogeny, 03 medical and health sciences, 0302 clinical medicine, Gene, Caspase, 030304 developmental biology, Original Paper, 0303 health sciences, Cell Growth Processe, biology, Animal, Regeneration (biology), Apoptosi, Protein Isoform, Cell biology, 030220 oncology & carcinogenesis, Mitogen-activated protein kinase, biology.protein, Signal transduction
Abstract

Irradiated or injured cells enter apoptosis, and in turn, promote proliferation of surrounding unaffected cells. In Drosophila, apoptotic cells have an active role in proliferation, where the caspase Dronc and p53 induce mitogen expression and growth in the surrounding tissues. The Drosophila p53 gene structure is conserved and encodes at least two protein isoforms: a full-length isoform (Dp53) and an N-terminally truncated isoform (DDNp53). Historically, DDNp53 was the first p53 isoform identified and was thought to be responsible for all p53 biological activities. It was shown that DDNp53 induces apoptosis by inducing the expression of IAP antagonists, such as Reaper. Here we investigated the roles of Dp53 and DDNp53 in apoptosis and apoptosis- induced proliferation. We found that both isoforms were capable of activating apoptosis, but that they each induced distinct IAP antagonists. Expression of DDNp53 induced Wingless (Wg) expression and enhanced proliferation in both ‘undead cells’ and in ‘genuine’ apoptotic cells. In contrast to DDNp53, Dp53 did not induce Wg expression in the absence of the endogenous p53 gene. Thus, we propose that DDNp53 is the main isoform that regulates apoptosis-induced proliferation. Understanding the roles of Drosophila p53 isoforms in apoptosis and in apoptosis-induced proliferation may shed new light on the roles of p53 isoforms in humans, with important implications in cancer biology.

Published
2012
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19. Structure of a DNA-bound Ultrabithorax-Extradenticle homeodomain complex.

Author

Passner JM, Ryoo HD, Shen L, Mann RS, and Aggarwal AK

Subjects
Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, DNA metabolism, DNA-Binding Proteins metabolism, Drosophila, Homeodomain Proteins metabolism, Insect Proteins chemistry, Insect Proteins metabolism, Macromolecular Substances, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Protein Binding, Protein Conformation, Transcription Factors metabolism, DNA chemistry, DNA-Binding Proteins chemistry, Drosophila Proteins, Homeodomain Proteins chemistry, Transcription Factors chemistry
Abstract

During the development of multicellular organisms, gene expression must be tightly regulated, both spatially and temporally. One set of transcription factors that are important in animal development is encoded by the homeotic (Hox) genes, which govern the choice between alternative developmental pathways along the anterior-posterior axis. Hox proteins, such as Drosophila Ultrabithorax, have low DNA-binding specificity by themselves but gain affinity and specificity when they bind together with the homeoprotein Extradenticle (or Pbxl in mammals). To understand the structural basis of Hox-Extradenticle pairing, we determine here the crystal structure of an Ultrabithorax-Extradenticle-DNA complex at 2.4 A resolution, using the minimal polypeptides that form a cooperative heterodimer. The Ultrabithorax and Extradenticle homeodomains bind opposite faces of the DNA, with their DNA-recognition helices almost touching each other. However, most of the cooperative interactions arise from the YPWM amino-acid motif of Ultrabithorax-located amino-terminally to its homeodomain-which forms a reverse turn and inserts into a hydrophobic pocket on the Extradenticle homeodomain surface. Together, these protein-DNA and protein-protein interactions define the general principles by which homeotic proteins interact with Extradenticle (or Pbx1) to affect development along the anterior-posterior axis of animals.

Published
1999
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20. Synergistic activation of a Drosophila enhancer by HOM/EXD and DPP signaling.

Author

Grieder NC, Marty T, Ryoo HD, Mann RS, and Affolter M

Subjects
Animals, Base Sequence, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins genetics, Dimerization, Genes, Insect, Insect Proteins biosynthesis, Insect Proteins genetics, Molecular Sequence Data, Mutagenesis, Site-Directed, Polymerase Chain Reaction, Recombinant Proteins biosynthesis, Recombinant Proteins metabolism, Signal Transduction, Transcription Factors biosynthesis, Transcription Factors genetics, Vertebrates, DNA-Binding Proteins metabolism, Drosophila Proteins, Drosophila melanogaster genetics, Enhancer Elements, Genetic, Genes, Homeobox, Homeodomain Proteins biosynthesis, Insect Proteins metabolism, Transcription Factors metabolism
Abstract

The homeotic proteins encoded by the genes of the Drosophila HOM and the vertebrate HOX complexes do not bind divergent DNA sequences with a high selectivity. In vitro, HOM (HOX) specificity can be increased by the formation of heterodimers with Extradenticle (EXD) or PBX homeodomain proteins. We have identified a single essential Labial (LAB)/EXD-binding site in a Decapentaplegic (DPP)-responsive enhancer of the homeotic gene lab which drives expression in the developing midgut. We show that LAB and EXD bind cooperatively to the site in vitro, and that the expression of the enhancer in vivo requires exd and lab function. In addition, point mutations in either the EXD or the LAB subsite compromise enhancer function, strongly suggesting that EXD and LAB bind to this site in vivo. Interestingly, we found that the activity of the enhancer is only stimulated by DPP signaling significantly upon binding of LAB and EXD. Thus, the enhancer appears to integrate positional information via the homeotic gene lab, and spatiotemporal information via DPP signaling; only when these inputs act in concert in an endodermal cell is the enhancer fully active. Our results illustrate how a tissue-specific response to DPP can be generated through synergistic effects on an enhancer carrying both DPP- and HOX-responsive sequences.

Published
1997
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21. Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein.

Author

Rieckhof GE, Casares F, Ryoo HD, Abu-Shaar M, and Mann RS

Subjects
Animal Structures physiology, Animals, Biological Transport genetics, Cell Nucleus chemistry, Cell Nucleus metabolism, Cytoplasm chemistry, DNA-Binding Proteins analysis, Embryo, Nonmammalian physiology, Embryonic and Fetal Development physiology, Gene Expression Regulation, Developmental, Genes, Homeobox physiology, Homeodomain Proteins metabolism, Leukemia, Myeloid, Mice, Molecular Sequence Data, Myeloid Ecotropic Viral Integration Site 1 Protein, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Sequence Homology, Amino Acid, Transcription Factors analysis, DNA-Binding Proteins metabolism, Drosophila Proteins, Drosophila melanogaster genetics, Homeodomain Proteins genetics, Transcription Factors metabolism
Abstract

We show that homothorax (hth) is required for the Hox genes to pattern the body of the fruit fly, Drosophila melanogaster. hth is necessary for the nuclear localization of an essential HOX cofactor, Extradenticle (EXD), and encodes a homeodomain protein that shares extensive identity with the product of Meis1, a murine proto-oncogene. MEIS1 is able to rescue hth mutant phenotypes and can induce the cytoplasmic-to-nuclear translocation of EXD in cell culture and Drosophila embryos. Thus, Meis1 is a murine homolog of hth. MEIS1/HTH also specifically binds to EXD with high affinity in vitro. These data suggest a novel and evolutionarily conserved mechanism for regulating HOX activity in which a direct protein-protein interaction between EXD and HTH results in EXD's nuclear translocation.

Published
1997
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