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Epidermal Wnt Signalling Regulates Transcriptome Heterogeneity and Proliferative Fate in Neighbouring Cells
bioRxiv preprint doi: https://doi.org/10.1101/152637; this version posted June 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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 4.0 International license. Title: Epidermal Wnt signalling regulates transcriptome heterogeneity and proliferative fate in neighbouring cells Arsham Ghahramani1,2 , Giacomo Donati2,3 , Nicholas M. Luscombe1,4,5,† and Fiona M. Watt2,† 1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, United Kingdom 2King’s College London, Centre for Stem Cells and Regenerative Medicine, 28th 8 Floor, Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, United Kingdom 3Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Torino, Italy 4UCL Genetics Institute, University College London, London WC1E 6BT, United Kingdom 5Okinawa Institute of Science & Technology Graduate University, Okinawa 904-0495, Japan † Correspondence to: [email protected] and [email protected] Abstract: Canonical Wnt/beta-catenin signalling regulates self-renewal and lineage selection within the mouse epidermis. Although the transcriptional response of keratinocytes that receive a Wnt signal is well characterised, little is known about the mechanism by which keratinocytes in proximity to the Wnt- receiving cell are co-opted to undergo a change in cell fate. To address this, we performed single-cell mRNA-Seq on mouse keratinocytes co-cultured with and without the presence of beta-catenin activated neighbouring cells. We identified seven distinct cell states in cultures that had not been exposed to the beta-catenin stimulus and show that the stimulus redistributes wild type subpopulation proportions. -
A Role for Mammalian Sin3 in Permanent Gene Silencing
Molecular Cell Article A Role for Mammalian Sin3 in Permanent Gene Silencing Chris van Oevelen,1 Jinhua Wang,1 Patrik Asp,1 Qin Yan,2,3 William G. Kaelin, Jr.,2,3 Yuval Kluger,1,* and Brian David Dynlacht1,* 1New York University School of Medicine, NYU Cancer Institute, 522 1st Avenue, New York, NY 10016, USA 2Howard Hughes Medical Institute 3Department of Medical Oncology Dana Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] (B.D.D.), [email protected] (Y.K.) DOI 10.1016/j.molcel.2008.10.015 SUMMARY substoichiometric regulatory proteins, including Swi/Snf-remod- eling proteins, retinoblastoma (RB)-binding protein 2 (RBP2), and The multisubunit Sin3 corepressor complex regu- other proteins (Hayakawa et al., 2007; Nagl et al., 2007; Sif et al., lates gene transcription through deacetylation of nu- 2001). Interestingly, RBP2 was recently shown to be a demethy- cleosomes. However, the full range of Sin3 activities lase specific for di- and trimethylated lysine 4 of histone H3 and targets is not well understood. Here, we have (Christensen et al., 2007; Klose et al., 2007). Thus, the Sin3 investigated genome-wide binding of mouse Sin3 complex provides a versatile platform for chromatin modifying and RBP2 as well as histone modifications and nucle- and remodeling activities. Sin3/Rpd3 corepressor complexes are recruited to promoter osome positioning as a function of myogenic differ- regions via sequence-specific repressors such as Ume6 or entiation. Remarkably, we find that Sin3 complexes Mad in yeast and mammalian cells, respectively, resulting in spread immediately downstream of the transcription localized deacetylation of histones within promoter regions and start site on repressed and transcribed genes during transcriptional silencing (Ayer et al., 1995; Kadosh and Struhl, differentiation. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Chromatin Modification and Disease
J Med Genet 2000;37:905–915 905 Chromatin modification and disease J Med Genet: first published as 10.1136/jmg.37.12.905 on 1 December 2000. Downloaded from Colin A Johnson “Physicians consider that when they have discov- plexes that bring about histone acetylation (the ered the cause of disease, they have also discovered family of histone acetyltransferases or HAT the method of treating it.” Cicero, Tusculan Dis- coactivators) and deacetylation (the histone putations, III.x.23. deacetylases or HDAC corepressors). This In the last few years, the exciting realisation review will focus on some of the clinical aspects in the field of gene regulation is that transcrip- of this recent work on acetylation and the inti- tion factors can function by recruiting large, mate connection that it is now known to have multiprotein complexes which mediate several with the methylation of cytosine residues in types of chromatin modification and remodel- DNA. A third type of chromatin remodelling is ling events that alter the structure of chroma- the direct physical repositioning or disruption tin. Chromatin structure changes include post- of nucleosomes mediated by a family of DNA translational modifications of histones, DNA dependent ATPases. The connection between methylation, remodelling of the chromatin, and this latter type of remodelling and either the maintenance of a heterochromatic or histone acetylation or DNA methylation is euchromatic state. Most of these events are complicated, but progress is being made. For brought about by enzymatic mechanisms. In example, the NuRD multiprotein complex (see general, the catalytic subunits are only one below, fig 1C) contains histone deacetylase and component of the complexes, with the distribu- chromatin remodelling activities, as well as the tion and localisation of the structural changes methyl DNA binding protein MBD3, which dependent on targeting components. -
PWWP2A Binds Distinct Chromatin Moieties and Interacts with an MTA1-Specific Core Nurd Complex
ARTICLE DOI: 10.1038/s41467-018-06665-5 OPEN PWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex Stephanie Link1,2, Ramona M.M. Spitzer1,2, Maryam Sana3, Mario Torrado3, Moritz C. Völker-Albert1, Eva C. Keilhauer4,9, Thomas Burgold5,10, Sebastian Pünzeler1,11, Jason K.K. Low3, Ida Lindström 3, Andrea Nist6, Catherine Regnard1, Thorsten Stiewe 6,7, Brian Hendrich5, Axel Imhof 1,8, Matthias Mann 4,8, Joel P. Mackay 3, Marek Bartkuhn2 & Sandra B. Hake 2,8 1234567890():,; Chromatin structure and function is regulated by reader proteins recognizing histone mod- ifications and/or histone variants. We recently identified that PWWP2A tightly binds to H2A. Z-containing nucleosomes and is involved in mitotic progression and cranial–facial devel- opment. Here, using in vitro assays, we show that distinct domains of PWWP2A mediate binding to free linker DNA as well as H3K36me3 nucleosomes. In vivo, PWWP2A strongly recognizes H2A.Z-containing regulatory regions and weakly binds H3K36me3-containing gene bodies. Further, PWWP2A binds to an MTA1-specific subcomplex of the NuRD complex (M1HR), which consists solely of MTA1, HDAC1, and RBBP4/7, and excludes CHD, GATAD2 and MBD proteins. Depletion of PWWP2A leads to an increase of acetylation levels on H3K27 as well as H2A.Z, presumably by impaired chromatin recruitment of M1HR. Thus, this study identifies PWWP2A as a complex chromatin-binding protein that serves to direct the deacetylase complex M1HR to H2A.Z-containing chromatin, thereby promoting changes in histone acetylation levels. 1 Department of Molecular Biology, BioMedical Center (BMC), Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany. -
Aberrations of EZH2 in Cancer
Published OnlineFirst March 2, 2011; DOI: 10.1158/1078-0432.CCR-10-2156 Clinical Cancer Molecular Pathways Research Aberrations of EZH2 in Cancer Andrew Chase and Nicholas C.P. Cross Abstract Control of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases, and histone deacetylases, resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumors, including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity, whereas inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients, but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation, resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors, opening up the possibility of refined epigenetic treatments in the future. Clin Cancer Res; 17(9); 2613–8. Ó2011 AACR. Background trithorax homolog myeloid-lymphoid leukemia (MLL), is associated with transcriptional activation (Fig. 1A). Impor- DNA is wrapped around histone complexes termed tantly, many genes involved in development, stem cell nucleosomes, and gene accessibility is determined largely maintenance, and differentiation are targets of H3K27 by the local chromatin configuration. -
Stress-Mediated Sin3b Activation Leads to Negative Regulation of Subset of P53 Target Genes
Biosci. Rep. (2015) / 35 / art:e00234 / doi 10.1042/BSR20150122 Stress-mediated Sin3B activation leads to negative regulation of subset of p53 target genes Rama Kadamb*1, Shilpi Mittal*, Nidhi Bansal* and Daman Saluja*1 *Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India Synopsis Downloaded from http://portlandpress.com/bioscirep/article-pdf/35/4/e00234/476914/bsr035e234.pdf by guest on 24 September 2021 The multiprotein SWI-independent 3 (Sin3)–HDAC (histone deacetylase) corepressor complex mediates gene re- pression through its interaction with DNA-binding factors and recruitment of chromatin-modifying proteins on to the promoters of target gene. Previously, an increased expression of Sin3B and tumour suppressor protein, p53 has been established upon adriamycin treatment. We, now provide evidence that Sin3B expression is significantly up-regulated under variety of stress conditions and this response is not stress-type specific. We observed that Sin3B expression is significantly up-regulated both at transcript and at protein level upon DNA damage induced by bleomycin drug, a radiomimetic agent. This increase in Sin3B expression upon stress is found to be p53-dependent and is associated with enhanced interaction of Sin3B with Ser15 phosphorylated p53. Binding of Sin3–HDAC repressor complex on to the promoters of p53 target genes influences gene regulation by altering histone modifications (H3K9me3 and H3K27me3) at target genes. Furthermore, knockdown of Sin3B by shRNA severely compromises p53-mediated gene repression under stress conditions. Taken together, these results suggest that stress-induced Sin3B activation is p53-dependent and is essential for p53-mediated repression of its selective target genes. -
Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence Anthony J
Published OnlineFirst August 14, 2017; DOI: 10.1158/0008-5472.CAN-16-3410 Cancer Tumor and Stem Cell Biology Research Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence Anthony J. Bainor1, Fang-Ming Deng2, Yu Wang1, Peng Lee2,4, David J. Cantor1, Susan K. Logan1,3,4, and Gregory David1,3,4 Abstract Distinguishing between indolent and aggressive prostate ade- cinoma. Furthermore, SIN3B was downregulated in human pros- nocarcinoma remains a priority to accurately identify patients tate adenocarcinoma correlating with upregulation of its target who need therapeutic intervention. SIN3B has been implicated in genes. Our results suggest a tumor suppressor function for the initiation of senescence in vitro. Here we show that in a mouse SIN3B that limits prostate adenocarcinoma progression, with model of prostate cancer, SIN3B provides a barrier to malignant potential implications for the use of SIN3B and its target genes progression. SIN3B was required for PTEN-induced cellular senes- as candidate diagnostic markers to distinguish indolent from cence and prevented progression to invasive prostate adenocar- aggressive disease. Cancer Res; 77(19); 1–10. Ó2017 AACR. Introduction damage, activation of oncogenes, or loss of a tumor suppres- sor (5, 6). Senescent cells have been identified in preneoplastic Prostate adenocarcinoma is the second most common cancer lesions of several solid tumor types, including prostatic intrae- type in American men with approximately 230,000 new pithelial neoplasias (PIN), but are rarely found in normal patients diagnosed each year, equating to about 1 in 7 men prostate or prostate adenocarcinoma (7). On the basis of these being diagnosed with prostate adenocarcinoma in his lifetime findings, cellular senescence has been hypothesized to prevent (1). -
Senescence-Associated SIN3B Promotes Inflammation and Pancreatic Cancer Progression
Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression Maïté Rielland, … , George Miller, Gregory David J Clin Invest. 2014;124(5):2125-2135. https://doi.org/10.1172/JCI72619. Research Article Oncology Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We previously demonstrated that the histone deacetylase–associated protein SIN3B is essential for oncogene-induced senescence in cultured cells. Here, using a mouse model of pancreatic cancer, we have demonstrated that SIN3B is required for activated KRAS-induced senescence in vivo. Surprisingly, impaired senescence as the result of genetic inactivation of Sin3B was associated with delayed PDAC progression and correlated with an impaired inflammatory response. In murine and human pancreatic cells and tissues, levels of SIN3B correlated with KRAS-induced production of IL-1α. Furthermore, evaluation of human pancreatic tissue and cancer cells revealed that Sin3B was decreased in control and PDAC samples, compared with samples from patients with pancreatic inflammation. These results indicate that senescence-associated inflammation positively correlates with PDAC progression and suggest that SIN3B has potential as a therapeutic target for inhibiting inflammation-driven tumorigenesis. Find the latest version: https://jci.me/72619/pdf Research article Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression Maïté Rielland,1 David J. Cantor,1 Richard Graveline,1 Cristina Hajdu,2 Lisa Mara,2 Beatriz de Diego Diaz,1 George Miller,3,4 and Gregory David1,5 1Department of Biochemistry and Molecular Pharmacology, 2Department of Pathology, 3Department of Surgery, 4Department of Cell Biology, and 5New York University (NYU) Cancer Institute, NYU School of Medicine, New York, New York, USA. -
2Czy Lichtarge Lab 2006
Pages 1–6 2czy Evolutionary trace report by report maker July 31, 2009 4.3.1 Alistat 5 4.3.2 CE 6 4.3.3 DSSP 6 4.3.4 HSSP 6 4.3.5 LaTex 6 4.3.6 Muscle 6 4.3.7 Pymol 6 4.4 Note about ET Viewer 6 4.5 Citing this work 6 4.6 About report maker 6 4.7 Attachments 6 1 INTRODUCTION From the original Protein Data Bank entry (PDB id 2czy): Title: Solution structure of the nrsf/rest-msin3b pah1 complex Compound: Mol id: 1; molecule: paired amphipathic helix protein sin3b; chain: a; fragment: pah1 domain (residues 31-107); synonym: sin3b, transcriptional corepressor sin3b, histone deacetylase complex subunit sin3b; engineered: yes; mol id: 2; molecule: transcription factor rest (version 3); chain: b; fragment: sin3 interaction domain (residues 43-57); synonym: nrsf/rest; engineered: yes CONTENTS Organism, scientific name: Mus Musculus; 2czy contains a single unique chain 2czyA (77 residues long). 1 Introduction 1 Chain 2czyB is too short (15 residues) to permit statistically signi- ficant analysis, and was treated as a peptide ligand. This is an 2 Chain 2czyA 1 NMR-determined structure – in this report the first model in the file 2.1 Q62141 overview 1 was used. 2.2 Multiple sequence alignment for 2czyA 1 2.3 Residue ranking in 2czyA 2 2 CHAIN 2CZYA 2.4 Top ranking residues in 2czyA and their position on 2.1 Q62141 overview the structure 2 2.4.1 Clustering of residues at 25% coverage. 2 From SwissProt, id Q62141, 100% identical to 2czyA: 2.4.2 Overlap with known functional surfaces at Description: Paired amphipathic helix protein Sin3b (Transcriptio- 25% coverage. -
Targeting Human Retinoblastoma Binding Protein 4 (RBBP4) and 7 (RBBP7)
bioRxiv preprint doi: https://doi.org/10.1101/303537; this version posted April 18, 2018. 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. Targeting Human Retinoblastoma Binding Protein 4 (RBBP4) and 7 (RBBP7) Megha Abbey1, Viacheslav Trush1, Elisa Gibson1, and Masoud Vedadi1,2* 1Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada 2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada To whom correspondence should be addressed: Masoud Vedadi; Tel.: 416-432-1980; E-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/303537; this version posted April 18, 2018. 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. Abstract RBBP4 and RBBP7 (RBBP4/7) are highly homologous nuclear WD40 motif containing proteins widely implicated in various cancers and are valuable drug targets. They interact with multiple proteins within diverse complexes such as NuRD and PRC2, as well as histone H3 and H4 through two distinct binding sites. FOG-1, PHF6 and histone H3 bind to the top of the donut shape seven-bladed β-propeller fold, while SUZ12, MTA1 and histone H4 bind to a pocket on the side of the WD40 repeats. Here, we briefly review these six interactions and present binding assays optimized for medium to high throughput screening. These assays enable screening of RBBP4/7 toward the discovery of novel cancer therapeutics. -
Global Analysis of Chromosome X Gene Expression in Primary Cultures of Normal Ovarian Surface Epithelial Cells and Epithelial Ovarian Cancer Cell Lines
5-17 6/12/06 18:21 Page 5 INTERNATIONAL JOURNAL OF ONCOLOGY 30: 5-17, 2007 5 Global analysis of chromosome X gene expression in primary cultures of normal ovarian surface epithelial cells and epithelial ovarian cancer cell lines MARIE-HÉLÈNE BENOÎT1, THOMAS J. HUDSON1,2,3, GEORGES MAIRE4, JEREMY A. SQUIRE4,5, SUZANNA L. ARCAND6, DIANE PROVENCHER7,8, ANNE-MARIE-MES-MASSON7,9 and PATRICIA N. TONIN1,3,6 1Department of Human Genetics, McGill University, Montreal, Quebec H3A 1A1; 2McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 1A4; 3Department of Medicine, McGill University, Montreal, Quebec H3G 1A4; 4Applied Molecular Oncology, The Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9; 5Departments of Medical Biophysics and Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5; 6The Research Institute of McGill University Health Center, Montreal, Quebec H3G 1A4; 7Centre de Recherche du Centre Hospitalier de l'Université de Montreal (CR-CHUM)/Institut du cancer de Montréal, Montreal, Quebec H2L 4M1; 8Division de gynécologie et obstétrique, and 9Départément de médicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada Received June 2, 2006; Accepted August 3, 2006 Abstract. The interpretation of loss of heterozygosity (LOH) and TOV21G. The combined evidence is consistent with two in cancers is complicated as genes that map to LOH regions proposed mechanisms to account for absence of Xi in female may be transcriptionally active (Xa) or inactive (Xi) due to X cancers: Xi loss followed by Xa duplication (exemplified by chromosome inactivation (XCI). We have analyzed the TOV112D) and transcriptional reactivation of Xi (exemplified chromosome X transcriptome in four epithelial ovarian by TOV21G).