DOCSLIB.ORG

Rel/NF-Kb Transcription Factors and Ikb Inhibitors: Evolution from a Unique Common Ancestor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Oncogene (1997) 15, 2965 ± 2974 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Rel/NF-kB transcription factors and IkB inhibitors: Evolution from a unique common ancestor Christelle Huguet1, Pascale Crepieux2 and Vincent Laudet2 1Laboratoire de reÂgulation des processus invasifs, de l'angiogeneÁse et de l'apoptose, EP560; 2Laboratoire des meÂcanismes du deÂveloppement et de la canceÂrisation, UMR319, IFR3 Institut de Biologie de Lille, 1 rue du Professeur Calmette, 59021 Lille, France From the sequences of Rel/NF-kB and IkB proteins, we 1995; Verma et al., 1995). Some of the Rel/NF-kB constructed an alignment of their Rel Homology Domain proteins, namely cRel, RelA, RelB/IRel, Dorsal and (RHD) and ankyrin repeat domain. Using this align- Dif (the `ready-to-use' members), contain a transacti- ment, we performed tree reconstruction with both vating domain in their C-terminal half (for references distance matrix and parsimony analysis and estimated see Table 1). The others, the p50 and p52 subunits, are the branching robustness using bootstrap resampling proteolytically maturated from the precursor proteins methods. We de®ned four subfamilies of Rel/NF-kB NF-kB1 (p105) and NF-kB2 (p100) respectively and transcription factors: (i) cRel, RelA, RelB, Dorsal and are devoid of transactivating domain (Table 1). Relish, Dif; (ii) NF-kB1 and NF-kB2; (iii) Relish and (iv) NF- a gene structurally related to NF-kB genes, has been AT factors, the most divergent members. Subfamilies I recently cloned in Drosophila (Dushay et al., 1996). and II are clustered together whereas Relish diverged Members of the Rel-NF-kB family bind DNA as homo earlier than other Rel/NF-kB proteins. Three subfamilies or heterodimers and recognize the consensus decameric of IkB inhibitors were also de®ned: (i) NF-kB1 and NF- sequence 5'-GGGPuNNPyPyCC-3' which is named kB kB2; (ii) close to subfamily I, the short IkB proteins site. Dierent kB sites among gene promoters are IkBa,IkBband Bcl-3; (iii) Relish that diverged earlier bound with dierent anities by the various dimers than other IkB inhibitors. Our de®nition of groups and which therefore bind certain target genes preferentially subfamilies ®ts to structural and functional features of (Chytil and Verdine, 1996; Miyamoto and Verma, the Rel/NF-kB and IkB proteins. We also showed that 1995; MuÈ ller et al., 1996). In addition, depending on ankyrin repeats of NF-kB1, NF-kB2 and Relish are the dimers, the transcription of the target gene is short IkB-speci®c ankyrin motifs. These proteins de®ning activated or repressed; for example RelA/p50, RelA/ a link between Rel/NF-kB and IkB families, we propose cRel, RelB/p50, RelB/p52 are potent transcriptional that all these factors evolved from a common ancestral activators, whereas p50/p50 or p52/p52 homodimers RHD-ankyrin structure within a unique superfamily, generally repress transcription (Siebenlist et al., 1994; explaining the speci®cities of interaction between the Verma et al., 1995). dierent Rel/NF-kB dimers and the various IkB The various Rel/NF-kB dimers are submitted to inhibitors. dierent regulations by inhibitors of the IkB family (Miyamoto and Verma, 1995). The IkB family is a Keywords: ankyrin repeat protein; rel homology subfamily of ankyrin repeat proteins including IkBa, domain; NF-AT; molecular phylogeny IkBb,IkBg, Bcl-3, NF-kB1 and NF-kB2. The NF-kB precursor proteins present ankyrin repeats in their C- terminal half thereby exhibiting IkB inhibitory func- tions (Siebenlist et al., 1994). The IkB proteins bind the Introduction various Rel/NF-kB dimers with dierent anities, and retain them in the cytoplasm (Miyamoto and Verma, Transcription factors represent key molecules that 1995). Activation of the Rel/NF-kB proteins requires convert signals received by the cell into activation or phosphorylation and subsequent degradation of the repression of genes that lead to cell responses such as IkB inhibitors, thus allowing the transcription complex proliferation, dierentiation or apoptosis. The Rel/NF- to translocate into the nucleus (Finco and Baldwin, kB transcription factors are involved in the immune 1995; Thanos and Maniatis, 1995; Verma et al., 1995). response, i.e. in immunoreceptor gene expression, Once in the nucleus, the Rel/NF-kB transcription cytokine and growth factor regulation, and also in factors will regulate the transcription of various target embryonic development and programmed cell death genes including their own genes in an autoregulatory (Baeuerle and Henkel, 1994; Huguet et al., 1994; loop, thus reconstituting the stocks of Rel/NF-kB Kabrun et al., 1990; Kopp and Ghosh, 1995). These proteins in the cytoplasm. Moreover, they will activate Rel/NF-kB proteins share a 300 amino acid N-terminal the transcription of their IkB inhibitors leading to the domain, named the Rel Homology Domain (RHD), production of new IkB proteins. The newly synthesized which harbors a DNA-binding region, a dimerization IkBa will terminate the activation of Rel/NF-kB domain, a nuclear localization signal and a region of factors by migrating into the nucleus and displacing interaction with inhibitory proteins of the IkB family the Rel/NF-kB dimers from the DNA. On the (Chytil and Verdine, 1996; Miyamoto and Verma, contrary, the newly synthesized IkBb will continue the activation by protecting the Rel/NF-kB dimers Correspondence: V Laudet from the inhibition of the newly synthesized IkBa Received 24 April 1997; revised 1 August 1997; accepted 1 August (Baeuerle and Baltimore, 1996; Gilmore et al., 1996; 1997 Miyamoto and Verma, 1995). Rel/NF-kBandIkBevolution CHuguetet al 2966 Table 1 Sequences used in this study. For each sequences, the Genbank code and the accession number, when dierent, were given as well as the reference. The sequences are given in the order of the distance trees (Figure 1 left panel) Gene species Databank accession Reference Rel/NF-kB Family Homo cRel HSRNAREL/X75042 (Brownell et al., 1989) Mus cRel MMCRELM/X15842 (Grumont and Gerondakis, 1989) Gallus cRel GSP68REL/X52193 (Capobianco et al., 1990) Meleagris cRel TKYREL09/K02455 (Wilhemsen et al., 1984) Viridae Rel ACRREL/K00555/X02759 (Wilhemsen et al., 1984) Xenopus Xrel2 XLREL2POR/Z49252 (Tannahill and Wardle, 1995) Homo RelA HUMP65NFKB/M62399 (Ruben et al., 1991) Mus RelA MUSNFKP65/M61909 (Nolan et al., 1991) Xenopus Xrel1 XELREL/M60785 (Kao and Hopwood, 1991) Gallus RelA CHKNFKB2/D13721 (Ikeda et al., 1993) Homo Irel HUMIRELA/M83221 (Ruben et al., 1992a) Mus RelB MUSRELB/M83380 (Ryseck et al., 1992) Xenopus RelB XLRELB/D63332 (Suzuki et al., 1995) Drosophila Dorsal DRODORSAL/M23702 (Steward, 1987) Drosophila Dif DRODIF/L29015 (Ip et al., 1993) Homo NF-kB1 HUMNFKB34/M55643/M37492 (Kieran et al., 1990) Mus NF-kB1 MUSTFDBS/M57999/M37732 (Ghosh et al., 1990) Gallus NF-kB1 CHKP105A/M86930 (Capobianco et al., 1992) Homo NF-kB2 S76638 (Bours et al., 1992) Gallus NF-kB2 U00111 (Sif and Gilmore, 1993) Drosophila Relish U62005 (Dushay et al., 1996) NF-AT Family Homo NF-AT3 HUMNFAT3A/L41066 (Hoey et al., 1995) Homo NF-AT4 HUMHFAT4A/L41067 (Hoey et al., 1995) Homo NF-ATx HSU14510/U14510 (Masuda et al., 1995) Homo NF-ATc HSU08015/U08015 (Northrop et al., 1994) Mus NF-ATp MMU02079/U02079 (McCarey et al., 1993) IkB Family Homo NF-kB1 HUMNFKB34/M55643/M37492 (Kieran et al., 1990) Mus NF-kB1 MUSTFDBS/M57999/M37732 (Ghosh et al., 1990) Gallus NF-kB1 CHKP105A/M86930 (Capobianco et al., 1992) Homo NF-kB2 S76638 (Bours et al., 1992) Gallus NF-kB2 U00111 (Sif and Gilmore, 1993) Drosophila Relish U62005 (Dushay et al., 1996) Homo IkBa HUMMAD3A/M69043 (Haskill et al., 1991) Sus IkBa SDECI6A/Z21968 (De Martin et al., 1993) Rattus IkBa RRRLIF1/X63594 (Tewari et al., 1992) Gallus IkBa CHKPP40 (Davis et al., 1991) Drosophila Cactus DROCACTUS/L04964 (Geisler et al., 1992) Mus IkBb MMU19799/U19799 (Thompson et al., 1995) Homo Bcl-3 HUMBCL3AA/M31732 (Ohno et al., 1990) Ankyrin Family Homo Ankyrin HUMANK/M28880 (Lambert et al., 1990) Mus Ankyrin 1 MMANK1AA/X69063 (Birkenmeier et al., 1993) Drosophila Ankyrin DROANKY/L35601 (Dubreuil and Yu, 1994) A large set of experimental data recently illustrated Results how sophisticated the relationships between the Rel/ NF-kB transcription factors and their IkB inhibitors Alignment of sequence of the Rel/NF-kB and IkB are: autoregulatory loops, proteins displaying both proteins the roles of transcription factor and inhibitor, various combinations of transcriptional and inhibitory part- In order to produce a complete list of all known full ners undergoing dierent regulations. In fact, the length sequences of the members of both the Rel/NF- combination of the Rel/NF-kB and IkB families kB and IkB families (Table 1), we performed several constitutes a powerful and tightly controlled path- searches in the Genbank and EMBL databases using way to respond to various stimuli and to mediate the FASTA program. Only complete cDNA sequences speci®c cell response. Therefore, it is important to were kept. Therefore, since we only found a 3' ¯anking understand how these two families of genes evolved region for the mouse Bcl-3 gene in the data banks and diversi®ed to reach such a level of speci®city and (accession number M90397) despite its cloning cited by autoregulation. To address this question, we studied Ito et al. (1994), it has not been included in this study. in parallel the molecular evolution of the Rel/NF-kB Thirty-seven sequences were retained in this analysis: and IkB proteins. This phylogenetical analysis 25 in the Rel/NF-kB family and 14 in the IkB family; allowed to de®ne the structure of the putative the NF-kB1, NF-kB2 and Relish sequences belong to ancestor genes and to propose an evolutionary both families. Three ankyrin genes (erythroid ankyrin model that clusters both families in a unique Rel/ or ankyrin 1) were chosen as an outgroup for the IkB NF-kB/IkB superfamily.
Recommended publications
  • Transcriptional Regulation by Extracellular Signals 209

    Transcriptional Regulation by Extracellular Signals 209

    Cell, Vol. 80, 199-211, January 27, 1995, Copyright © 1995 by Cell Press Transcriptional Regulation Review by Extracellular Signals: Mechanisms and Specificity Caroline S. Hill and Richard Treisman Nuclear Translocation Transcription Laboratory In principle, regulated nuclear localization of transcription Imperial Cancer Research Fund factors can involve regulated activity of either nuclear lo- Lincoln's Inn Fields calization signals (NLSs) or cytoplasmic retention signals, London WC2A 3PX although no well-characterized case of the latter has yet England been reported. N LS activity, which is generally dependent on short regions of basic amino acids, can be regulated either by masking mechanisms or by phosphorylations Changes in cell behavior induced by extracellular signal- within the NLS itself (Hunter and Karin, 1992). For exam- ing molecules such as growth factors and cytokines re- ple, association with an inhibitory subunit masks the NLS quire execution of a complex program of transcriptional of NF-KB and its relatives (Figure 1; for review see Beg events. While the route followed by the intracellular signal and Baldwin, 1993), while an intramolecular mechanism from the cell membrane to its transcription factor targets may mask NLS activity in the heat shock regulatory factor can be traced in an increasing number of cases, how the HSF2 (Sheldon and Kingston, 1993). When transcription specificity of the transcriptional response of the cell to factor localization is dependent on regulated NLS activity, different stimuli is determined is much less clear. How- linkage to a constitutively acting NLS may be sufficient to ever, it is possible to understand at least in principle how render nuclear localization independent of signaling (Beg different stimuli can activate the same signal pathway yet et al., 1992).
  • Ankrd9 Is a Metabolically-Controlled Regulator of Impdh2 Abundance and Macro-Assembly

    Ankrd9 Is a Metabolically-Controlled Regulator of Impdh2 Abundance and Macro-Assembly

    ANKRD9 IS A METABOLICALLY-CONTROLLED REGULATOR OF IMPDH2 ABUNDANCE AND MACRO-ASSEMBLY by Dawn Hayward A dissertation submitted to The Johns Hopkins University in conformity with the requirements of the degree of Doctor of Philosophy Baltimore, Maryland April 2019 ABSTRACT Members of a large family of Ankyrin Repeat Domains proteins (ANKRD) regulate numerous cellular processes by binding and changing properties of specific protein targets. We show that interactions with a target protein and the functional outcomes can be markedly altered by cells’ metabolic state. ANKRD9 facilitates degradation of inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in GTP biosynthesis. Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 by binding to vesicles. Upon nutrient limitation, ANKRD9 loses association with vesicles and assembles with IMPDH2 into rod-like structures, in which IMPDH2 is stable. Inhibition of IMPDH2 with Ribavirin favors ANKRD9 binding to rods. The IMPDH2/ANKRD9 assembly is reversed by guanosine, which restores association of ANKRD9 with vesicles. The conserved Cys109Cys110 motif in ANKRD9 is required for the vesicles-to-rods transition as well as binding and regulation of IMPDH2. ANKRD9 knockdown increases IMPDH2 levels and prevents formation of IMPDH2 rods upon nutrient limitation. Thus, the status of guanosine pools affects the mode of ANKRD9 action towards IMPDH2. Advisor: Dr. Svetlana Lutsenko, Department of Physiology, Johns Hopkins University School of Medicine Second reader:
  • NF-Κb Modifies the Mammalian Circadian Clock Through Interaction with the Core Clock Protein BMAL1

    NF-Κb Modifies the Mammalian Circadian Clock Through Interaction with the Core Clock Protein BMAL1

    bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.285254; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1 Yang Shen1, Wei Wang2, Mehari Endale1, Lauren J. Francey3, Rachel L. Harold4, David W. Hammers5, Zhiguang Huo6, Carrie L. Partch4, John B. Hogenesch3, Zhao-Hui Wu2, and Andrew C. Liu1* 1Department of Physiology and Functional Genomics, University of Florida College of Medicine; 2Department of Radiation Oncology and Center for Cancer Research, University of Tennessee Health Science Center; 3Divisions of Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center; 4Department of Chemistry and Biochemistry, University of California Santa Cruz; 5Department of Pharmacology and Therapeutics, University of Florida College of Medicine; 6Department of Biostatistics, College of Public Health & Health Professions, University of Florida College of Medicine Running title: NF-κB modifies circadian clock * Correspondence: Andrew C. Liu, [email protected] Keywords: Circadian clock, inflammation, NF-κB, suprachiasmatic nucleus (SCN), BMAL1 Abbreviations: NF-κB, nuclear factor kappa B; SCN, suprachiasmatic nucleus; IKK, IκB kinase; IκBα, inhibitor of NF-κB; Luc, luciferase; RHD, Rel homology domain; CRD, C-terminal oscillation regulatory domain, TAD, transactivation domain 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.06.285254; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved.
  • Repeat Proteins Challenge the Concept of Structural Domains

    Repeat Proteins Challenge the Concept of Structural Domains

    844 Biochemical Society Transactions (2015) Volume 43, part 5 Repeat proteins challenge the concept of structural domains Rocıo´ Espada*1, R. Gonzalo Parra*1, Manfred J. Sippl†, Thierry Mora‡, Aleksandra M. Walczak§ and Diego U. Ferreiro*2 *Protein Physiology Lab, Dep de Qu´ımica Biologica, ´ Facultad de Ciencias Exactas y Naturales, UBA-CONICET-IQUIBICEN, Buenos Aires, C1430EGA, Argentina †Center of Applied Molecular Engineering, Division of Bioinformatics, Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria ‡Laboratoire de physique statistique, CNRS, UPMC and Ecole normale superieure, ´ 24 rue Lhomond, 75005 Paris, France §Laboratoire de physique theorique, ´ CNRS, UPMC and Ecole normale superieure, ´ 24 rue Lhomond, 75005 Paris, France Abstract Structural domains are believed to be modules within proteins that can fold and function independently. Some proteins show tandem repetitions of apparent modular structure that do not fold independently, but rather co-operate in stabilizing structural forms that comprise several repeat-units. For many natural repeat-proteins, it has been shown that weak energetic links between repeats lead to the breakdown of co-operativity and the appearance of folding sub-domains within an apparently regular repeat array. The quasi-1D architecture of repeat-proteins is crucial in detailing how the local energetic balances can modulate the folding dynamics of these proteins, which can be related to the physiological behaviour of these ubiquitous biological systems. Introduction and between repeats, challenging the concept of structural It was early on noted that many natural proteins typically domain. collapse stretches of amino acid chains into compact units, defining structural domains [1]. These domains typically correlate with biological activities and many modern proteins can be described as composed by novel ‘domain arrange- Definition of the repeat-units ments’ [2].
  • The Co-Activator-Like Mediator Complex Forms a Molecular Bridge Between Activation Domains and Pol II

    The Co-Activator-Like Mediator Complex Forms a Molecular Bridge Between Activation Domains and Pol II

    The Co-activator-like Mediator Complex Forms a Molecular Bridge Between Activation Domains and Pol II Co-activator the general problem example of several upstream activators interacting with a single co-activator-like mediator complex Transcription Regulation And Gene Expression in Eukaryotes FS 2016 Graduate Course G2 P. Matthias and RG Clerc Pharmazentrum Hörsaal 2 16h15-18h00 REGULATORY MECHANISMS OF TRANSCRIPTION FACTOR FUNCTION •Protein synthesized •Protein phosphorylated •Ligand binding •Release inhibitor •Change partner, etc RG Clerc April 6. 2016 Transcription factors as final effectors of the cellular signaling cascade Regulatory Mechanisms of Transcription Factor Function Genes X. Lewin B. editor Regulatory Mechanisms of Transcription Factor Function CREB FOXO NFAT Genes X. Lewin B. editor Body plan is constructed through interactions of the developmentally regulated homeotic gene expression anterior early expression posterior late expression high RA response low RA response hindbrain trunk Alexander T and Krumlauf R. Ann.Rev.Cell.Dev.Biol: 25_431 (2009) Hoxb transcription factors mRNA distribution along the AP axis A staggered expression of the anterior border within somites is a property of the physical ordering along the chromosome: the colinearity Alexander T and Krumlauf R. Ann.Rev.Cell.Dev.Biol: 25_431 (2009) Transcription control of the Hox genes: insight into colinear activation P A p p p p a p a p a a a a Tarchini B and Duboule D. Dev.Cell 10_93 (2006) correlation between linear arrangement along the chromosome and spatial
  • A Structural Guide to Proteins of the NF-Kb Signaling Module

    A Structural Guide to Proteins of the NF-Kb Signaling Module

    Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press A Structural Guide to Proteins of the NF-kB Signaling Module Tom Huxford1 and Gourisankar Ghosh2 1Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, California 92182-1030 2Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0375 Correspondence: [email protected] The prosurvival transcription factor NF-kB specifically binds promoter DNA to activate target gene expression. NF-kB is regulated through interactions with IkB inhibitor proteins. Active proteolysis of these IkB proteins is, in turn, under the control of the IkB kinase complex (IKK). Together, these three molecules form the NF-kB signaling module. Studies aimed at charac- terizing the molecular mechanisms of NF-kB, IkB, and IKK in terms of their three-dimen- sional structures have lead to a greater understanding of this vital transcription factor system. F-kB is a master transcription factor that from the perspective of their three-dimensional Nresponds to diverse cell stimuli by activat- structures. ing the expression of stress response genes. Multiple signals, including cytokines, growth factors, engagement of the T-cell receptor, and NF-kB bacterial and viral products, induce NF-kB Introduction to NF-kB transcriptional activity (Hayden and Ghosh 2008). A point of convergence for the myriad NF-kB was discovered in the laboratory of of NF-kB inducing signals is the IkB kinase David Baltimore as a nuclear activity with bind- complex (IKK). Active IKK in turn controls ing specificity toward a ten-base-pair DNA transcription factor NF-kB by regulating pro- sequence 50-GGGACTTTCC-30 present within teolysis of the IkB inhibitor protein (Fig.
  • Supp. Table S2: Domains and Protein Families with a Putative Role in Host-Symbiont Interactions

    Supp. Table S2: Domains and Protein Families with a Putative Role in Host-Symbiont Interactions

    Supp. Table S2: Domains and protein families with a putative role in host-symbiont interactions. The domains and protein families listed here were included in the comparisons in Figure 5 and Supp. Figure S5, which show the percentage of the respective protein groups in the Riftia symbiont metagenome and in metagenomes of other symbiotic and free-living organisms. % bacterial, total number bacterial: Percentage and total number of bacterial species in which this domain is found in the SMART database (January 2019). Domain name Pfam/SMART % bacterial (total Literature/comment annotation number bacterial) Alpha-2- alpha-2- A2M: 42.05% (2057) A2Ms: protease inhibitors which are important for eukaryotic macroglobulin macroglobulin innate immunity, if present in prokaryotes apparently fulfill a family (A2M), similar role, e.g. protection against host proteases (1) including N- terminal MG1 domain ANAPC Anaphase- APC2: 0 Ubiquitin ligase, important for cell cycle control in eukaryotes (2) promoting complex Bacterial proteins might interact with ubiquitination pathways in subunits the host (3) Ankyrin Ankyrin repeats 10.88% (8348) Mediate protein-protein interactions without sequence specificity (4) Sponge symbiont ankyrin-repeat proteins inhibit amoebal phagocytosis (5) Present in sponge microbiome metatranscriptomes, putative role in symbiont-host interactions (6) Present in obligate intracellular amoeba symbiont Candidatus Amoebophilus asiaticus genome, probable function in interactions with the host (7) Armadillo Armadillo repeats 0.83% (67)
  • The C-Rel Transcription Factor and B-Cell Proliferation: a Deal with the Devil

    The C-Rel Transcription Factor and B-Cell Proliferation: a Deal with the Devil

    Oncogene (2004) 23, 2275–2286 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc REVIEW The c-Rel transcription factor and B-cell proliferation: a deal with the devil Thomas D Gilmore*,1, Demetrios Kalaitzidis1, Mei-Chih Liang1 and Daniel T Starczynowski1 1Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA Activation of the Rel/NF-jB signal transduction pathway called the Rel homology domain, which has sequences has been associated with a varietyof animal and human required for DNA binding, dimerization, nuclear malignancies. However, among the Rel/NF-jB family localization, and inhibitor (IkB) binding. Sequences members, onlyc-Rel has been consistentlyshown to be C-terminal to the Rel homology domain in c-Rel, RelA, able to malignantlytransform cells in culture. In addition, and RelB contain transcriptional activation domains, c-rel has been activated bya retroviral promoter insertion and therefore dimers that contain these Rel/NF-kB in an avian B-cell lymphoma, and amplifications of REL members usually increase transcription of target genes. (human c-rel) are frequentlyseen in Hodgkin’s lympho- Although the Rel homology domain sequences of c-Rel mas and diffuse large B-cell lymphomas, and in some proteins across species are highly conserved, their follicular and mediastinal B-cell lymphomas. Phenotypic C-terminal transactivation domains are not. For exam- analysis of c-rel knockout mice demonstrates that c-Rel ple, the Rel homology domains of chicken and human has a normal role in B-cell proliferation and survival; c-Rel are approximately 85% identical, whereas their moreover, c-Rel nuclear activityis required for B-cell C-terminal transactivation domains are only about 10% development.
  • The Role of Ubiquitination in NF-Κb Signaling During Virus Infection

    The Role of Ubiquitination in NF-Κb Signaling During Virus Infection

    viruses Review The Role of Ubiquitination in NF-κB Signaling during Virus Infection Kun Song and Shitao Li * Department of Microbiology and Immunology, Tulane University, New Orleans, LA 70112, USA; [email protected] * Correspondence: [email protected] Abstract: The nuclear factor κB (NF-κB) family are the master transcription factors that control cell proliferation, apoptosis, the expression of interferons and proinflammatory factors, and viral infection. During viral infection, host innate immune system senses viral products, such as viral nucleic acids, to activate innate defense pathways, including the NF-κB signaling axis, thereby inhibiting viral infection. In these NF-κB signaling pathways, diverse types of ubiquitination have been shown to participate in different steps of the signal cascades. Recent advances find that viruses also modulate the ubiquitination in NF-κB signaling pathways to activate viral gene expression or inhibit host NF-κB activation and inflammation, thereby facilitating viral infection. Understanding the role of ubiquitination in NF-κB signaling during viral infection will advance our knowledge of regulatory mechanisms of NF-κB signaling and pave the avenue for potential antiviral therapeutics. Thus, here we systematically review the ubiquitination in NF-κB signaling, delineate how viruses modulate the NF-κB signaling via ubiquitination and discuss the potential future directions. Keywords: NF-κB; polyubiquitination; linear ubiquitination; inflammation; host defense; viral infection Citation: Song, K.; Li, S. The Role of 1. Introduction Ubiquitination in NF-κB Signaling The nuclear factor κB (NF-κB) is a small family of five transcription factors, including during Virus Infection. Viruses 2021, RelA (also known as p65), RelB, c-Rel, p50 and p52 [1].
  • And C-Terminal Domains of Relb Are Required for Full Transactivation

    And C-Terminal Domains of Relb Are Required for Full Transactivation

    MOLECULAR AND CELLULAR BIOLOGY, Mar. 1993, p. 1572-1582 Vol. 13, No. 3 0270-7306/93/031572-11$02.00/0 Copyright © 1993, American Society for Microbiology Both N- and C-Terminal Domains of RelB Are Required for Full Transactivation: Role of the N-Terminal Leucine Zipper-Like Motif PAWEL DOBRZANSKI, ROLF-PETER RYSECK, AND RODRIGO BRAVO* Department ofMolecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000 Received 18 September 1992/Returned for modification 11 November 1992/Accepted 12 December 1992 RelB, a member of the Rel family of transcription factors, can stimulate promoter activity in the presence of p50-NF-KB or p5OB/p49-NF-KB in mammalian cells. Transcriptional activation analysis reveals that the N and C termini of RelB are required for full transactivation in the presence of p50-NF-KB. RelB/p50-NF-KB hybrid molecules containing the Rel homology domain of p50-NF-KB and the N and C termini of RelB have high transcriptional activity compared with wild-type p50-NF-KB. The N and C termini of RelB cooperate in transactivation in cis or trans configuration. Alterations in the structure of the leucine zipper-like motif present in the N terminus of RelB significantly decrease the transcriptional capacity of RelB and of different RelB/p50-NF-KB hybrid molecules. Serum stimulation of quiescent fibroblasts induces the regulated by the inhibitory factor cactus (28). The different expression of more than 100 genes, including several proto- homodimers and heterodimers formed between the members oncogenes encoding for transcriptional factors belonging to of the Rel family regulate gene expression in vivo (20, 22, 42) the Jun, Fos, and Rel families (2, 11, 13, 24, 34-36, 38).
  • Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant

    Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant

    Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7,
  • WSB1: from Homeostasis to Hypoxia Moinul Haque1,2,3, Joseph Keith Kendal1,2,3, Ryan Matthew Macisaac1,2,3 and Douglas James Demetrick1,2,3,4*

    WSB1: from Homeostasis to Hypoxia Moinul Haque1,2,3, Joseph Keith Kendal1,2,3, Ryan Matthew Macisaac1,2,3 and Douglas James Demetrick1,2,3,4*

    Haque et al. Journal of Biomedical Science (2016) 23:61 DOI 10.1186/s12929-016-0270-3 REVIEW Open Access WSB1: from homeostasis to hypoxia Moinul Haque1,2,3, Joseph Keith Kendal1,2,3, Ryan Matthew MacIsaac1,2,3 and Douglas James Demetrick1,2,3,4* Abstract The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson’s Disease, via an unusual mode of protein ubiquitinylation. WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.