DOCSLIB.ORG

Arthritis Rheumatoid Disease Severity in Patients with B, Is Associated

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Arthritis Rheumatoid Disease Severity in Patients with B, Is Associated A Truncated Variant of ASCC1, a Novel Inhibitor of NF- κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis This information is current as of September 25, 2021. Silvia Torices, Lorena Alvarez-Rodríguez, Lara Grande, Ignacio Varela, Pedro Muñoz, Dora Pascual, Alejandro Balsa, Marcos López-Hoyos, Víctor Martinez-Taboada and Jose L. Fernández-Luna J Immunol 2015; 195:5415-5420; Prepublished online 26 Downloaded from October 2015; doi: 10.4049/jimmunol.1501532 http://www.jimmunol.org/content/195/11/5415 http://www.jimmunol.org/ References This article cites 28 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/195/11/5415.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Truncated Variant of ASCC1, a Novel Inhibitor of NF-kB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis Silvia Torices,*,† Lorena Alvarez-Rodrı´guez,* Lara Grande,† Ignacio Varela,‡ Pedro Mun˜oz,x Dora Pascual,{ Alejandro Balsa,{ Marcos Lo´pez-Hoyos,‖ Vı´ctor Martinez-Taboada,*,# and Jose L. Ferna´ndez-Luna† Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-kB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-kB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-kB target genes (TRAIL, TNF-a, cIAP-1, IL8) and blocks activation of a NF-kB–luciferase reporter construct in five different human cell Downloaded from lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-kB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-kB and the secretion of TNF-a in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheu- matic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated http://www.jimmunol.org/ allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-kB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA. The Journal of Immunology, 2015, 195: 5415–5420. heumatoid arthritis (RA) is an autoimmune disease char- There is increasing evidence that NF-kB is a major, if not the acterized by progressive joint destruction caused by the main, transcription factor controlling inflammation (5). Activation of R chronic inflammation of the synovial tissue (1, 2). Al- the NF-kB pathway is involved in the pathogenesis of chronic in- by guest on September 25, 2021 though several genes have been suggested to be associated with flammatory disorders, including RA and inflammatory bowel disease RA, the genetic regulation that contributes to the development of (6, 7). NF-kB proteins are regulated by the inhibitor of NF-kBki- disease in these patients remains unclear (3, 4). nase (IkB) complex formed by inhibitor of NF-k kinase (IKK)a and IKKb and the regulatory subunit IKKg. This kinase complex phosphorylates IkB, which is subsequently ubiquitinated and de- *Servicio de Reumatologı´a, Hospital Universitario Marques de Valdecilla-Instituto de graded, thus leading to the activation of NF-kB (8, 9). In addition, Investigacio´n Valdecilla, 39011 Santander, Spain; †Unidad de Gene´tica, Hospital Uni- some members of the nucleotide-binding domain and leucine-rich versitario Marques de Valdecilla-Instituto de Investigacio´n Valdecilla, 39011 Santander, Spain; ‡Servicio de Reumatologı´a, Hospital Universitario La Paz, 08046 Madrid, repeat containing (NLR) family including NOD1, NOD2, NLR Spain; xSeccio´n de Inmunologı´a, Hospital Universitario Marques de Valdecilla- pyrindomaincontaining(NLRP)3,andNLRP2regulatetheactivity { Instituto de Investigacio´n Valdecilla, 39011 Santander, Spain; Instituto de Biomedicina of NF-kB (10, 11). Aberrant NF-kB signaling has been described y Biotecnologı´a de Cantabria (Universidad de Cantabria, Consejo Superior de Inves- tigaciones Cientı´ficas), 39011 Santander, Spain; ‖Gerencia Atencio´n Primaria, Servicio in various cancers and immune diseases. Gene variants of IKKb Ca´ntabro de Salud, 39011 Santander, Spain; and #Facultad de Medicina, Universidad de have been associated with colorectal cancer (12), lymphomas, mul- Cantabria, 39011 Santander, Spain tiple myeloma (13), and combined immunodeficiency (14). Previous ORCIDs: 0000-0002-0969-506X (I.V.); 0000-0002-1387-2655 (P.M.); 0000-0001- 8070-7062 (A.B.). work has also identified variants of MYD88 and TNFRSF11A that promote constitutive activation of NF-kB (15, 16). Our group has Received for publication July 8, 2015. Accepted for publication September 27, 2015. previously described that a truncating variant that abrogates the ca- This work was supported by the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation Grants PI11/02012 and RD12/0036/0022 from Red Tema´tica pacity of CARD8 to inhibit the NF-kB transcriptional activity is de Investigacio´n Cooperativa en Ca´ncer, Federacio´n Espan˜ola de Reumatologı´a associated with disease severity in RA patients (17). Grant FER13/13, Instituto de Investigacio´n Valdecilla Grant APG-03, and the pro- grama Ramo´n y Cajal, Ministerio de Economia y Competitividad, Spain (I.V.). ASCC1 encodes the p50 subunit of a protein complex, which includes ASCC2, ASCC3, and TRIP4 (also known as ASC1), Address correspondence and reprint requests to Dr. Jose L. Fernandez-Luna, Unidad de Gene´tica, Hospital Universitario Marques de Valdecilla-Instituto de Investigacio´n among others (18) involved in transcriptional regulation. TRIP4 Valdecilla, Avenida Cardenal Herrera Oria, 39011 Santander, Spain. E-mail address: contains a transactivation domain with a putative zinc finger motif, fl[email protected] which serves as a binding site for TATA-binding protein, TFIIA, Abbreviations used in this article: DMARD, disease-modifying antirheumatic drug; HUMV, Hospital Universitario Marques de Valdecilla; IkB, inhibitor of NF-kB ki- SRC1, CBP/p300, and nuclear receptors (19). It also interacts with nase; IKK, inhibitor of NF-k kinase; NGS, next-generation sequencing; NLR, nucleo- a wide range of transcription factors including serum response tide-binding domain and leucine-rich repeat containing; NLRP, NLR pyrin domain factor, NF-kB, and AP1, and has been shown to be part of a containing; RA, rheumatoid arthritis; SNP, single nucleotide polymorphism. coactivator complex that links these factors to the transcriptional Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 machinery (18). Overexpressed TRIP4 has been normally local- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501532 5416 AN ASCC1 VARIANT ASSOCIATES WITH SEVERITY IN RA ized in the nucleus but accumulates in the cytoplasm under serum- ASCC1 was selected and analyzed in the other 367 patients with RA and deprived conditions (19). Thus, it is suggested that TRIP4 plays 184 age-matched control individuals. DNA was extracted from whole an important role in establishing distinct coactivator complexes blood by using the QIAamp DNA blood kit (Qiagen, Hamburg, Germany) and amplified with primers for human ASCC1: 59-TGAGGACTCATGG- under different cellular conditions (19). Very little is known about CAACAGC-39 and 59-ACTTGATAGCCCTGTGATGGC-39.Sequenceanal- the association between other members of the ASCC1-containing ysis of amplified fragments was carried out by Sanger sequencing. complex and disease. A recent study described a germline missense Expression analyses of NF-kB target genes mutation in exon 8 of ASCC1 (p.N290S) in patients with Barrett esophagus and esophageal adenocarcinoma (20), but no functional To assess the expression of individual genes, we generated and amplified a cDNA studies were shown. by using primers for human TNF-a (59-CAATGGCGTGGAGCTGAGAG-39 and 59-GGCTGATGGTGTGGGTGAGG-39), CCL2 (59-CTCGCTCAGCCA- A number of studies suggest that NF-kB is essential for the GATGCAAT-39 and 59-GTCTTCGGAGTTTGGGTTTGC-39), IL-8 (59-CTGG expression of both inflammatory cytokines and tissue-destructive
Load more

Recommended publications
  • A Steroid Receptor Coactivator Stimulator (MCB-613) Attenuates Adverse Remodeling After Myocardial Infarction
    A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction Lisa K. Mullanya,1, Aarti D. Rohiraa,1, John P. Leachb,2, Jong H. Kimc,d,2, Tanner O. Monroec, Andrea R. Ortiza, Brittany Storka, M. Waleed Gabere, Poonam Sarkare, Andrew G. Sikoraf, Todd K. Rosengartg, Brian Yorka, Yongcheng Songh, Clifford C. Dacsoa, David M. Lonarda, James F. Martinc,d,3, and Bert W. O’Malleya,3 aDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; bPenn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, TX 77030; dCardiomyocyte Renewal Lab, Texas Heart Institute, Houston, TX 77030; eDepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030; fDepartment of Otolaryngology-Head & Neck Surgery, Baylor College of Medicine, Houston, TX 77030; gDepartment of Surgery, Baylor College of Medicine, Houston, TX 77030; and hDepartment of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030 Contributed by Bert W. O’Malley, September 16, 2020 (sent for review June 23, 2020; reviewed by Chris Glass and Philip W. Shaul) Progressive remodeling of the heart, resulting in cardiomyocyte maintenance of metabolic regulation in diverse organ systems (CM) loss and increased inflammation, fibrosis, and a progressive including the heart (16). Specifically in the heart, recent findings decrease in cardiac function, are hallmarks of myocardial infarction indicate that SRC family members regulate cardiomyocyte func- (MI)-induced heart failure. We show that MCB-613, a potent small tion during early cardiac development (17) and in response to molecule stimulator of steroid receptor coactivators (SRCs) atten- cardiac metabolic stress (18).
    [Show full text]
  • Discovery of Osmotic Sensitive Transcription Factors in Fish Intestine Via a Transcriptomic Approach
    Wong et al. BMC Genomics 2014, 15:1134 http://www.biomedcentral.com/1471-2164/15/1134 RESEARCH ARTICLE Open Access Discovery of osmotic sensitive transcription factors in fish intestine via a transcriptomic approach Marty Kwok-Shing Wong1*, Haruka Ozaki2, Yutaka Suzuki2, Wataru Iwasaki1,2,3 and Yoshio Takei1 Abstract Background: Teleost intestine is crucial for seawater acclimation by sensing osmolality of imbibed seawater and regulating drinking and water/ion absorption. Regulatory genes for transforming intestinal function have not been identified. A transcriptomic approach was used to search for such genes in the intestine of euryhaline medaka. Results: Quantitative RNA-seq by Illumina Hi-Seq Sequencing method was performed to analyze intestinal gene expression 0 h, 1 h, 3 h, 1 d, and 7 d after seawater transfer. Gene ontology (GO) enrichment results showed that cell adhesion, signal transduction, and protein phosphorylation gene categories were augmented soon after transfer, indicating a rapid reorganization of cellular components and functions. Among >50 transiently up-regulated transcription factors selected via co-expression correlation and GO selection, five transcription factors, including CEBPB and CEBPD, were confirmed by quantitative PCR to be specific to hyperosmotic stress, while others were also up-regulated after freshwater control transfer, including some well-known osmotic-stress transcription factors such as SGK1 and TSC22D3/ Ostf1. Protein interaction networks suggest a high degree of overlapping among the signaling of transcription factors that respond to osmotic and general stresses, which sheds light on the interpretation of their roles during hyperosmotic stress and emergency. Conclusions: Since cortisol is an important hormone for seawater acclimation as well as for general stress in teleosts, emergency and osmotic challenges could have been evolved in parallel and resulted in the overlapped signaling networks.
    [Show full text]
  • S41467-020-18249-3.Pdf
    ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
    [Show full text]
  • Efficient Analysis of Mouse Genome Sequences Reveal Many Nonsense Variants
    Efficient analysis of mouse genome sequences reveal many nonsense variants Sophie Steelanda,b,1, Steven Timmermansa,b,1, Sara Van Ryckeghema,b, Paco Hulpiaua,b, Yvan Saeysa,c, Marc Van Montagud,e,f,2, Roosmarijn E. Vandenbrouckea,b,3, and Claude Liberta,b,2,3 aInflammation Research Center, Flanders Institute for Biotechnology (VIB), 9052 Ghent, Belgium; bDepartment of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium; cDepartment of Internal Medicine, Ghent University, 9052 Ghent, Belgium; dDepartment of Plant Systems Biology, VIB, 9052 Ghent, Belgium; eDepartment of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Ghent, Belgium; and fInternational Plant Biotechnology Outreach, VIB, Ghent, Belgium Contributed by Marc Van Montagu, March 30, 2016 (sent for review December 31, 2015; reviewed by Bruce Beutler, Stefano Bruscoli, Stefan Rose-John, and Klaus Schulze-Osthoff) Genetic polymorphisms in coding genes play an important role alive, archiving them, and distributing mutant strains to in- when using mouse inbred strains as research models. They have terested users (4). been shown to influence research results, explain phenotypical Since Clarence Little showed in the early 20th century that the differences between inbred strains, and increase the amount of principle of inbreeding also applies to mice, several hundred interesting gene variants present in the many available inbred inbred mouse strains have been generated (5). Some of these lines. SPRET/Ei is an inbred strain derived from Mus spretus that strains display specific phenotypes that are the result of a mutant has ∼1% sequence difference with the C57BL/6J reference ge- gene, and in several cases have formed the basis for identifying nome.
    [Show full text]
  • SUPPLEMENTARY NOTE Co-Activation of GR and NFKB
    SUPPLEMENTARY NOTE Co-activation of GR and NFKB alters the repertoire of their binding sites and target genes. Nagesha A.S. Rao1*, Melysia T. McCalman1,*, Panagiotis Moulos2,4, Kees-Jan Francoijs1, 2 2 3 3,5 Aristotelis Chatziioannou , Fragiskos N. Kolisis , Michael N. Alexis , Dimitra J. Mitsiou and 1,5 Hendrik G. Stunnenberg 1Department of Molecular Biology, Radboud University Nijmegen, the Netherlands 2Metabolic Engineering and Bioinformatics Group, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece 3Molecular Endocrinology Programme, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Greece 4These authors contributed equally to this work 5 Corresponding authors E-MAIL: [email protected] ; TEL: +31-24-3610524; FAX: +31-24-3610520 E-MAIL: [email protected] ; TEL: +30-210-7273741; FAX: +30-210-7273677 Running title: Global GR and NFKB crosstalk Keywords: GR, p65, genome-wide, binding sites, crosstalk SUPPLEMENTARY FIGURES/FIGURE LEGENDS AND SUPPLEMENTARY TABLES 1 Rao118042_Supplementary Fig. 1 A Primary transcript Mature mRNA TNF/DMSO TNF/DMSO 8 12 r=0.74, p< 0.001 r=0.61, p< 0.001 ) 2 ) 10 2 6 8 4 6 4 2 2 0 Fold change (mRNA) (log Fold change (primRNA) (log 0 −2 −2 −2 0 2 4 −2 0 2 4 Fold change (RNAPII) (log2) Fold change (RNAPII) (log2) B chr5: chrX: 56 _ 104 _ DMSO DMSO 1 _ 1 _ 56 _ 104 _ TA TA 1 _ 1 _ 56 _ 104 _ TNF TNF Cluster 1 1 _ Cluster 2 1 _ 56 _ 104 _ TA+TNF TA+TNF 1 _ 1 _ CCNB1 TSC22D3 chr20: chr17: 25 _ 33 _ DMSO DMSO 1 _ 1 _ 25 _ 33 _ TA TA 1 _ 1 _ 25 _ 33 _ TNF TNF Cluster 3 1 _ Cluster 4 1 _ 25 _ 33 _ TA+TNF TA+TNF 1 _ 1 _ GPCPD1 CCL2 chr6: chr22: 77 _ 35 _ DMSO DMSO 1 _ 77 _ 1 _ 35 _ TA TA 1 _ 1 _ 77 _ 35 _ TNF Cluster 5 Cluster 6 TNF 1 _ 1 _ 77 _ 35 _ TA+TNF TA+TNF 1 _ 1 _ TNFAIP3 DGCR6 2 Supplementary Figure 1.
    [Show full text]
  • Full Text (PDF)
    The Journal of Immunology Enhancer Turnover Is Associated with a Divergent Transcriptional Response to Glucocorticoid in Mouse and Human Macrophages Alasdair W. Jubb,*,†,1 Robert S. Young,*,1 David A. Hume,† and Wendy A. Bickmore* Phenotypic differences between individuals and species are controlled in part through differences in expression of a relatively con- served set of genes. Genes expressed in the immune system are subject to especially powerful selection. We have investigated the evolution of both gene expression and candidate enhancers in human and mouse macrophages exposed to glucocorticoid (GC), a regulator of innate immunity and an important therapeutic agent. Our analyses revealed a very limited overlap in the repertoire of genes responsive to GC in human and mouse macrophages. Peaks of inducible binding of the GC receptor (GR) detected by chro- matin immunoprecipitation-Seq correlated with induction, but not repression, of target genes in both species, occurred at distal regulatory sites not promoters, and were strongly enriched for the consensus GR-binding motif. Turnover of GR binding between mice and humans was associated with gain and loss of the motif. There was no detectable signal of positive selection at species- specific GR binding sites, but clear evidence of purifying selection at the small number of conserved sites. We conclude that enhancer divergence underlies the difference in transcriptional activation after GC treatment between mouse and human macrophages. Only the shared inducible loci show evidence of selection, and therefore these loci may be important for the subset of responses to GC that is shared between species. The Journal of Immunology, 2016, 196: 813–822.
    [Show full text]
  • Insights Into Functional Connectivity in Mammalian Signal Transduction Pathways by Pairwise
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.30.891200; this version posted December 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Insights into Functional Connectivity in Mammalian Signal Transduction Pathways by Pairwise Comparison of Protein Interaction Partners of Critical Signaling Hubs Chilakamarti V. Ramana * Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA *Correspondence should be addressed: Chilakamarti V .Ramana, Telephone. (603)-738-2507, E-mail: [email protected] ORCID ID: /0000-0002-5153-8252 1 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.30.891200; this version posted December 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Growth factors and cytokines activate signal transduction pathways and regulate gene expression in eukaryotes. Intracellular domains of activated receptors recruit several protein kinases as well as transcription factors that serve as platforms or hubs for the assembly of multi-protein complexes. The signaling hubs involved in a related biologic function often share common interaction proteins and target genes. This functional connectivity suggests that a pairwise comparison of protein interaction partners of signaling hubs and network analysis of common partners and their expression analysis might lead to the identification of critical nodes in cellular signaling.
    [Show full text]
  • Glucocorticoid Receptor and Klf4 Co-Regulate Anti-Inflammatory Genes in Keratinocytes
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Digital.CSIC Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes Lisa M. Sevilla1, Víctor Latorre1,2, Elena Carceller1, Julia Boix1, Daniel Vodák3, Ian Geoffrey Mills4, 5, 6, and Paloma Pérez1 1 Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV- CSIC), Jaime Roig 11, E-46010 Valencia, Spain. 2 Faculty of Human and Medical Sciences, The University of Manchester, Manchester UK 3 Bioinformatics Core Facility, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Norway 4 Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway 5 Department of Cancer Prevention, Oslo University Hospitals, Oslo, Norway. 6 Department of Urology, Oslo University Hospitals, Oslo, Norway. Corresponding autor and person to whom reprint requests should be addressed: Paloma Pérez, PhD Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas (IBV- CSIC) Jaime Roig 11, E-46010, Valencia, Spain Phone: +34-96-339-1766 Fax: +34-96-369-0800 e-mail: [email protected] Grants and fellowships supporting the writing of paper: SAF2011-28115 of the Ministerio de Economía y Competitividad from the Spanish government. EC and JB are recipients of FPU and FPI fellowships of the Spanish Ministery, respectively Disclosure Statement: The authors have nothing to disclose. Abstract The glucocorticoid (GC) receptor (GR) and Kruppel-like factor Klf4 are transcription factors that play major roles in the skin homeostasis by regulating the expression of overlapping gene subsets.
    [Show full text]
  • GILZ-Dependent Modulation of Mtorc1 Regulates Spermatogonial Maintenance Hue M
    © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev165324. doi:10.1242/dev.165324 STEM CELLS AND REGENERATION RESEARCH ARTICLE GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance Hue M. La1,2,*, Ai-Leen Chan1,2,*, Julien M. D. Legrand1,2, Fernando J. Rossello1,2, Christina G. Gangemi1,2, Antonella Papa3, Qiang Cheng4, Eric F. Morand4 and Robin M. Hobbs1,2,‡ ABSTRACT prospermatogonia) upon migration to the basement membrane of Male fertility is dependent on spermatogonial stem cells (SSCs) that the seminiferous cords. The undifferentiated population contains self-renew and produce differentiating germ cells. Growth factors isolated spermatogonia (A-single or As) plus chains of cells produced within the testis are essential for SSC maintenance interconnected by cytoplasmic bridges. Two-cell chains are but intrinsic factors that dictate the SSC response to these stimuli known as A-paired (Apr) whereas chains of four or more cells are poorly characterised. Here, we have studied the role of GILZ, are known as A-aligned (Aal). Lineage-tracing studies demonstrate α a TSC22D family protein and spermatogenesis regulator, in that SSCs are marked by GFR 1 and typically As and Apr,whereas spermatogonial function and signalling. Although broadly expressed most undifferentiated cells, particularly Aal, are committed in the germline, GILZ was prominent in undifferentiated spermatogonia progenitors and marked by NGN3 (Hara et al., 2014; Nakagawa + and Gilz deletion in adults resulted in exhaustion of the GFRα1+ et al., 2010). NGN3 Aal may revert to SSCs through chain SSC-containing population and germline degeneration. GILZ loss fragmentation, particularly upon tissue damage (Nakagawa et al., γ was associated with mTORC1 activation, suggesting enhanced 2010).
    [Show full text]
  • TSC22D3 (NM 001015881) Human Tagged ORF Clone Product Data
    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 RG214246 TSC22D3 (NM_001015881) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: TSC22D3 (NM_001015881) Human Tagged ORF Clone Tag: TurboGFP Symbol: TSC22D3 Synonyms: DIP; DSIPI; GILZ; TSC-22R Vector: pCMV6-AC-GFP (PS100010) E. coli Selection: Ampicillin (100 ug/mL) Cell Selection: Neomycin ORF Nucleotide >RG214246 representing NM_001015881 Sequence: Red=Cloning site Blue=ORF Green=Tags(s) TTTTGTAATACGACTCACTATAGGGCGGCCGGGAATTCGTCGACTGGATCCGGTACCGAGGAGATCTGCC GCCGCGATCGCC ATGAACACCGAAATGTATCAGACCCCCATGGAGGTGGCGGTCTACCAGCTGCACAATTTCTCCATCTCCT TCTTCTCTTCTCTGCTTGGAGGGGATGTGGTTTCCGTTAAGCTGGACAACAGTGCCTCCGGAGCCAGCGT GGTGGCCATAGACAACAAGATCGAACAGGCCATGGATCTGGTGAAGAATCATCTGATGTATGCTGTGAGA GAGGAGGTGGAGATCCTGAAGGAGCAGATCCGAGAGCTGGTGGAGAAGAACTCCCAGCTAGAGCGTGAGA ACACCCTGTTGAAGACCCTGGCAAGCCCAGAGCAGCTGGAGAAGTTCCAGTCCTGTCTGAGCCCTGAAGA GCCAGCTCCCGAATCCCCACAAGTGCCCGAGGCCCCTGGTGGTTCTGCGGTG ACGCGTACGCGGCCGCTCGAG - GFP Tag - GTTTAA Protein Sequence: >RG214246 representing NM_001015881 Red=Cloning site Green=Tags(s) MNTEMYQTPMEVAVYQLHNFSISFFSSLLGGDVVSVKLDNSASGASVVAIDNKIEQAMDLVKNHLMYAVR EEVEILKEQIRELVEKNSQLERENTLLKTLASPEQLEKFQSCLSPEEPAPESPQVPEAPGGSAV TRTRPLE - GFP Tag - V Restriction Sites: SgfI-MluI This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies,
    [Show full text]
  • Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation
    MINI REVIEW published: 07 August 2019 doi: 10.3389/fimmu.2019.01823 Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation Lorenza Cannarile, Domenico V. Delfino, Sabrina Adorisio, Carlo Riccardi and Emira Ayroldi* Section of Pharmacology, Department of Medicine, Medical School, University of Perugia, Perugia, Italy Glucocorticoid-induced leucine zipper (GILZ) is a protein with multiple biological roles that is upregulated by glucocorticoids (GCs) in both immune and non-immune cells. Importantly, GCs are immunosuppressive primarily due to their regulation of cell signaling pathways that are crucial for immune system activity. GILZ, which is transcriptionally induced by the glucocorticoid receptor (GR), mediates part of these immunosuppressive, and anti-inflammatory effects, thereby controlling immune cell proliferation, survival, and differentiation. The primary immune cells targeted by the immunosuppressive activity of GCs are T cells. Importantly, the effects of GCs on T cells are partially Edited by: Massimo Gadina, mediated by GILZ. In fact, GILZ regulates T-cell activation, and differentiation by binding National Institute of Arthritis and and inhibiting factors essential for T-cell function. For example, GILZ associates with Musculoskeletal and Skin Diseases nuclear factor-κB (NF-κB), c-Fos, and c-Jun and inhibits NF-κB-, and AP-1-dependent (NIAMS), United States transcription. GILZ also binds Raf and Ras, inhibits activation of Ras/Raf downstream Reviewed by: Marc Pallardy, targets, including mitogen-activated protein kinase 1 (MAPK1). In addition GILZ inhibits Université Paris-Sud, France forkhead box O3 (FoxO3) without physical interaction. GILZ also promotes the activity of Géraldine Schlecht-Louf, Université Paris-Sud, France regulatory T cells (Tregs) by activating transforming growth factor-β (TGF-β) signaling.
    [Show full text]
  • Single Cell Analysis Reveals X Chromosome Upregulation Is Not
    bioRxiv preprint doi: https://doi.org/10.1101/2021.07.18.452817; this version posted July 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Single cell analysis reveals X chromosome upregulation is not global and 2 primarily belongs to ancestral genes in pre-gastrulation embryos 3 Naik C H, Chandel D, and Gayen S* 4 Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, 5 Bangalore-560012, India. 6 *Correspondence: [email protected] 7 8 Abstract 9 Recent studies have provided substantial evidence supporting Ohno's hypothesis that 10 upregulation of active X chromosome genes balances the dosage of X-linked gene expression 11 relative to autosomal genes. However, the dynamics of X-chromosome upregulation (XCU) 12 during early development remain poorly Pre-gastrulation embryos E6.50 13 understood. Here, we have profiled the E6.25 E5.5 14 dynamics of XCU in different lineages of 15 female pre-gastrulation mouse embryos at 16 single cell level through allele-specific single 17 cell RNA-seq analysis. We found dynamic 18 XCU upon initiation of random X- Epiblast cells 19 chromosome inactivation (XCI) in epiblast Onset of Random X-inactivation 20 cells and cells of extraembryonic lineages, 21 which undergo imprinted XCI, also harbored 22 upregulated active-X chromosome. On the 23 other hand, the extent of XCU remains 24 controversial till date.
    [Show full text]