DOCSLIB.ORG

Thesis Reference

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Thesis Reference Thesis Analyse de l'expression de BARD1 dans le cancer du poumon et le cancer colorectal ZHANG, Yong Qiang Abstract Les cancers du poumon et colorectaux sont les types de cancers les plus fréquents et les plus mortels. Plusieurs marqueurs pronostiques et prédictifs pour le cancer du poumon, de type "non-small cell lung cancer" (NSCLC), ont été identifiés récemment, parmi eux, BRCA1. BRCA1 est un suppresseur de tumeur, qui joue un rôle dans la réparation de l'ADN et dans la division cellulaire. La stabilité de la protéine BRCA1 dépend de son interaction avec une autre protéine, nommée BARD1. L'hétérodimère BARD1-BRCA1 a une activité d'ubiquitine-ligase E3, qui est responsable de toutes les fonctions oncosuppressives de BRCA1. Nous avons donc étudié l'expression de BARD1 et de BRCA1 dans des tissus de 100 cas de NSCLC et de 140 cas de cancers colorectaux. Des analyses par immuno-histochimie, basées sur la comparaison de plusieurs anticorps détectant des régions différentes de la protéine BARD1, ont mis en évidence que des formes de BARD1 aberrantes, mais pas la bona fide BARD1, sont exprimées dans ces cancers. Or, l'expression d'aucun antigène de BARD1 ne démontrait une corrélation avec l'expression de BRCA1. [...] Reference ZHANG, Yong Qiang. Analyse de l'expression de BARD1 dans le cancer du poumon et le cancer colorectal. Thèse de doctorat : Univ. Genève, 2010, no. Méd. 10625 URN : urn:nbn:ch:unige-118800 DOI : 10.13097/archive-ouverte/unige:11880 Available at: http://archive-ouverte.unige.ch/unige:11880 Disclaimer: layout of this document may differ from the published version. 1 / 1 Section de médecine Clinique Département de Gynécologie et Obstétrique Laboratoire de Gynécologie et Obstétrique Moléculaire Thèse préparée sous la direction du Professeur Olivier Irion et du Docteur Irmgard Irminger-Finger Analyse de l'expression de BARD1 dans le Cancer du Poumon et le Cancer Colorectal Thèse présentée à la Faculté de Médecine de l'Université de Genève pour obtenir le grade de Docteur en médecine par Yong Qiang ZHANG de Beijing (Chine) Thèse n° 10625 Genève 2010 i Dedicated specifically to My wife and my daughter, for supporting my study abroad wholeheartedly ii ACKNOWLEDGEMENTS In the first place, I would like to record my gratitude to my thesis supervisor, Dr. Irmgard Irminger-Finger, for her supervision, advice, and guidance of this research, as well as giving me extraordinary experiences throughout my two-year work and study. I sincerely express my thanks to Professor Olivier Irion for being my thesis director and for welcoming me to the Laboratory of Molecular Gynecology and Obstetrics. It is them who lead me into a science research world, which is very different from my clinical work field. Thanks for the help and support in both study and life during my stay in Geneva. I would like to thank Professor Paul Bischof and Professor Werner Schlegel for accepting to be my thesis jury. I would like to give credit to all previous and present members of the Laboratory of Molecular Gynecology and Obstetrics who helped me in various ways: specifically Dr. Eva Dizin-Bernabeu, and all others, Arwen Conod, Luciana Romano, Furaha Detraz, Filippo Molica, Dan Liu, Lin Li, JianYu Wu. I gratefully thank Dr. S Picciau, and Professor Luigi Atzuri, Andrea Bianco, Alvin M. Malkinson, and Regine Schneider-Stock for their precious collaboration. Great thanks to Dr. Michel Boulvain for his excellent support and help with the statistical analysis. Many thanks to Dr. Jean-Claude Pache for the help with his expertise on pathology. Last but not least, I also would like to thank Dr. Marie Cohen for her kindness and support, and Alice Neequaye for her joyous accompany and support. iii Investigation of BARD1 Expression in Non-Small Cell Lung Cancer and Colorectal Cancer CONTENTS Page I. Abbreviations 1 II. Summary in French 2 III. Introduction in French 4 IV. Summary in English 9 V. Introduction in English 11 1. BARD1 and its diverse functions 11 1.1. Structure of BARD1 11 1.2. Tissue distribution and cellular localization of BARD1 14 1.3. BARD1 knockout in animals and plants 16 1.4. Biological functions of BARD1 17 1.4.1. BRCA1-dependent functions of BARD1 17 1.4.1.1. Functions of the BRCA1-BARD1 heterodimer 17 1.4.1.2. Formation and regulation of BRCA1-BARD1 activity 19 1.4.1.3. The BRCA1-BARD1 targets and their associated functions 19 1.4.2. BRCA1-independent functions of BARD1 26 1.4.2.1. BARD1 and p53 26 1.4.2.2. BARD1 and NF-κB 29 1.5. Genetic and epigenetic modifications of BARD1 in cancer 30 1.5.1. BARD1 mutations, polymorphisms and cancer 30 1.5.2. BARD1 spliced isoforms and cancer 33 2. Cancers investigated in this study 36 2.1. Cancer occurrence and classification 36 iv 2.2. Non-small cell lung cancer 38 2.3. Colorectal cancer 39 3. Background of this study 40 VI. Materials and methods 46 1. Patients characteristics 46 1.1. Non-small cell lung cancer patients 46 1.2. Colorectal cancer patients 48 2. Mouse model of lung cancer 49 3. Immunohistochemistry 49 3.1. Immunohistostaining 49 3.2. Analysis and semi-quantitation of immunohistochemistry 50 4. Reverse transcription and PCR 51 5. DNA purification, cloning and sequencing 52 6. Statistical analysis 53 VII. Results 54 1. Investigation of BARD1 expression in human NSCLC 54 1.1. All NSCLC samples express BARD1 epitopes 54 1.2. Non-coordinate expression of BARD1 and BRCA1 59 1.3. BARD1 isoforms more expressed in tumor than peri-tumor tissues and more elevated in female than male patients 59 1.4. Correlation of BARD1 protein expression with clinicopathological characteristics and patients prognosis 62 1.5. Sequential expression of BARD1 epitopes at different stages of tumorigenesis in a mouse model of lung cancer 68 1.6. Structure of BARD1 isoforms expressed in NSCLC 70 2. Investigation of BARD1 expression in colorectal cancer 75 2.1. BARD1 protein level expressed in colorectal cancer samples 75 2.2. Non-coordinate expression of BARD1 and BRCA1 80 2.3. Correlation of BARD1 protein expression with clinicopathological characteristics and patients prognosis 81 v 2.4. Structure of BARD1 isoforms expressed in colorectal cancer 83 2.5. Similar BARD1 expression patterns observed in tissues from males and females 85 VIII. Discussion 88 IX. Perspectives and goals 93 X. Conclusions 94 XI. References 95 XII. Appendix 107 vi Abbreviations AJCC American Joint Committee on Cancer ANK Ankyrin domain BARD1 BRCA1-associated RING domain protein 1 BRCA1 Breast cancer susceptibility gene 1 BRCA2 Breast cancer susceptibility gene 2 BRCT BRCA1 carboxy-terminal domain DAB Diaminobenzidine tetrahydrocholoride DFS Disease-free survival DSBs Double strand breaks EGFR Epidermal growth factor receptor EtBr Ethidium bromide FL Full length GAPDH Glyceraldehyde-3-phosphate dehydrogenase IHC Immunohistochemistry MW Molecular weight NES Nuclear export signal NLS Nuclear localization signal NSCLC Non-small cell lung cancer OS Overall survival RING RING (really interesting new gene) domain RT-PCR Reverse transcription polymerase chain reaction SNP Single-nucleotide polymorphism WHO World health organization 1 Résumé Les cancers du poumon et colorectaux sont les types de cancers les plus fréquents et les plus mortels. Plusieurs marqueurs pronostiques et prédictifs pour le cancer du poumon, de type "non-small cell lung cancer" (NSCLC), ont été identifiés récemment, parmi eux, BRCA1. BRCA1 est un suppresseur de tumeur, qui joue un rôle dans la réparation de l’ADN et dans la division cellulaire. La stabilité de la protéine BRCA1 dépend de son interaction avec une autre protéine, nommée BARD1. L’hétérodimère BARD1-BRCA1 a une activité d’ubiquitine-ligase E3, qui est responsable de toutes les fonctions oncosuppressives de BRCA1. Nous avons donc étudié l’expression de BARD1 et de BRCA1 dans des tissus de 100 cas de NSCLC et de 140 cas de cancers colorectaux. Des analyses par immuno-histochimie, basées sur la comparaison de plusieurs anticorps détectant des régions différentes de la protéine BARD1, ont mis en évidence que des formes de BARD1 aberrantes, mais pas la bona fide BARD1, sont exprimées dans ces cancers. Or, l’expression d’aucun antigène de BARD1 ne démontrait une corrélation avec l’expression de BRCA1. Ceci suggère que la fonction d’ubiquitine-ligase E3 de l’hétéromère BARD1-BRCA1 soit compromise dans des cellules de ces cancers. Nous avons déterminé la structure des ARN messagers de BARD1 de 20 cas de NSCLC et 20 cas de cancer colorectaux. En plus des isoformes que nous avions décrites auparavant dans des cancer gynécologiques, nous avons identifié deux nouvelles formes de BARD1, les isoformes κ et π, dans des tumeurs de NSCLC et colorectales. Toutes les isoformes étaient surproduites exclusivement dans les tumeurs colorectales, par contre, pour NSCLC, toutes les formes de BARD1 étaient exprimées dans la tumeur et dans le tissu normal adjacent avec l’exception de l’isoforme π, qu’on ne trouvait que dans les tissus tumoraux. Ceci suggère que l’expression des isoformes de BARD1 serait modulée par des facteurs dépendant du type de tissu et de pathologie. L’expression de BARD1, ainsi que de BRCA1, peuvent être modulées par les oestrogènes via le récepteur aux oestrogènes (ER). Nous avons trouvé que ER-α était exprimé dans des tissus de poumons mais pas colorectaux. Il est donc possible que BARD1 joue un rôle 2 dans la voie de signalisation des oestrogènes, qui est soupçonnée d’être responsable de la prédisposition élevée des femmes au cancer des poumons. Il est très intéressant, que l’expression des différentes combinaisons d’isoformes soit corrélée au pronostique du patient. Ainsi, l’expression des epitopes encodés par l’exon 3 et le début de l’exon 4, qui est compatible avec l’expression de l’isoforme π, est corrélée avec un mauvais pronostique chez les patients de NSCLC et de cancer colorectaux.
Load more

Recommended publications
  • Identification and Characterization of TPRKB Dependency in TP53 Deficient Cancers
    Identification and Characterization of TPRKB Dependency in TP53 Deficient Cancers. by Kelly Kennaley A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Cellular Pathology) in the University of Michigan 2019 Doctoral Committee: Associate Professor Zaneta Nikolovska-Coleska, Co-Chair Adjunct Associate Professor Scott A. Tomlins, Co-Chair Associate Professor Eric R. Fearon Associate Professor Alexey I. Nesvizhskii Kelly R. Kennaley [email protected] ORCID iD: 0000-0003-2439-9020 © Kelly R. Kennaley 2019 Acknowledgements I have immeasurable gratitude for the unwavering support and guidance I received throughout my dissertation. First and foremost, I would like to thank my thesis advisor and mentor Dr. Scott Tomlins for entrusting me with a challenging, interesting, and impactful project. He taught me how to drive a project forward through set-backs, ask the important questions, and always consider the impact of my work. I’m truly appreciative for his commitment to ensuring that I would get the most from my graduate education. I am also grateful to the many members of the Tomlins lab that made it the supportive, collaborative, and educational environment that it was. I would like to give special thanks to those I’ve worked closely with on this project, particularly Dr. Moloy Goswami for his mentorship, Lei Lucy Wang, Dr. Sumin Han, and undergraduate students Bhavneet Singh, Travis Weiss, and Myles Barlow. I am also grateful for the support of my thesis committee, Dr. Eric Fearon, Dr. Alexey Nesvizhskii, and my co-mentor Dr. Zaneta Nikolovska-Coleska, who have offered guidance and critical evaluation since project inception.
    [Show full text]
  • BRE Facilitates Skeletal Muscle Regeneration by Promoting Satellite Cell Motility and Differentiation Lihai Xiao and Kenneth Ka Ho Lee*
    © 2016. Published by The Company of Biologists Ltd | Biology Open (2016) 5, 100-111 doi:10.1242/bio.012450 RESEARCH ARTICLE BRE facilitates skeletal muscle regeneration by promoting satellite cell motility and differentiation Lihai Xiao and Kenneth Ka Ho Lee* ABSTRACT formed myofibers will further fuse with existing intact myofibers The function of the Bre gene in satellite cells was investigated during to repair the damaged muscle. The extent of this bioactivity is skeletal muscle regeneration. The tibialis anterior leg muscle depending on the severity of injury. In vitro, it is possible to follow was experimentally injured in Bre knockout mutant (BRE-KO) mice. the chronological and dynamic process of satellite cell migration, ’ It was established that the accompanying muscle regeneration was differentiation and fusion (O Connor et al., 2007; Bae et al., 2008). impaired as compared with their normal wild-type counterparts (BRE- Many proteins have been now identified to be important in the WT). There were significantly fewer pax7+ satellite cells and smaller regulation of satellite cell migration which includes: fibroblast newly formed myofibers present in the injury sites of BRE-KO mice. growth factor (FGF), hepatocyte growth factor (HGF) and IL-4 Bre was required for satellite cell fusion and myofiber formation. The (Lluri and Jaworski, 2005; Lafreniere et al., 2006). Components of cell fusion index and average length of newly-formed BRE-KO the extracellular matrix (such as fibronectin and laminin) and α myofibers were found to be significantly reduced as compared with chemokines (such as SDF-1 ) also play important roles in BRE-WT myofibers.
    [Show full text]
  • A Computational Model for Classification of BRCA2 Variants Using Mouse Embryonic Stem Cell-Based Functional Assays
    www.nature.com/npjgenmed ARTICLE OPEN A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays Kajal Biswas1,5, Gary B. Lipton2,5, Stacey Stauffer1, Teresa Sullivan1, Linda Cleveland1, Eileen Southon1,3, Susan Reid1, ✉ ✉ Valentin Magidson4, Edwin S. Iversen Jr. 2 and Shyam K. Sharan 1 Sequencing-based genetic tests to identify individuals at increased risk of hereditary breast and ovarian cancers have resulted in the identification of more than 40,000 sequence variants of BRCA1 and BRCA2. A majority of these variants are considered to be variants of uncertain significance (VUS) because their impact on disease risk remains unknown, largely due to lack of sufficient familial linkage and epidemiological data. Several assays have been developed to examine the effect of VUS on protein function, which can be used to assess their impact on cancer susceptibility. In this study, we report the functional characterization of 88 BRCA2 variants, including several previously uncharacterized variants, using a well-established mouse embryonic stem cell (mESC)- based assay. We have examined their ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. We have also examined the impact of BRCA2 variants on splicing. In addition, we have developed a computational model to determine the probability of impact on function of the variants that can be used for risk assessment. In contrast to the previous VarCall models that are based on a single functional assay, we have developed a new platform to analyze the data from multiple functional assays separately and in combination.
    [Show full text]
  • BRCC3 Acts As a Prognostic Marker in Nasopharyngeal
    Tu et al. Radiation Oncology (2015) 10:123 DOI 10.1186/s13014-015-0427-3 RESEARCH Open Access BRCC3 acts as a prognostic marker in nasopharyngeal carcinoma patients treated with radiotherapy and mediates radiation resistance in vitro Ziwei Tu1,2, Bingqing Xu1,2, Chen Qu1,2, Yalan Tao1,2, Chen Chen1,2, Wenfeng Hua2, Guokai Feng2, Hui Chang1, Zhigang Liu3, Guo Li4, Changbin Jiang5, Wei Yi5, Musheng Zeng2 and Yunfei Xia1,2* Abstract Background: BRCC3 has been found to be aberrantly expressed in breast tumors and involved in DNA damage response. The contribution of BRCC3 to nasopharyngeal carcinoma prognosis and radiosensitivity is still unclear. Methods: Immunohistochemical analysis of BRCC3 was carried out in 100 nasopharyngeal carcinoma tissues, and the protein level was correlated to patient survival. BRCC3 expression of nasopharyngeal carcinoma cell lines was determined by Western-blotting and real-time PCR. Additionally, the effects of BRCC3 knockdown on nasopharyngeal carcinoma cell clongenic survival, DNA damage repair, and cell cycle distribution after irradiation was assessed. Results: The BRCC3 protein level was inversely correlated with nasopharyngeal carcinoma patient overall survival (P < 0.001) and 3-year loco-regional relapse-free survival (P = 0.034). Multivariate analysis demonstrated that BRCC3 expression was an independent prognostic factor (P = 0.010). The expression of BRCC3 was much higher in radioresistant nasopharyngeal carcinoma cells than in radiosensitive cells. Knockdown of BRCC3 increased the cell survival fraction, attenuated DNA damage repair and resulted in G2/M cell cycle arrest in radioresistant NPC cells. Conclusions: High BRCC3 expression in nasopharyngeal carcinoma patients is associated with poor survival.
    [Show full text]
  • Novel BRCA1 Mutations and More Frequent Intron-20 Alteration Found Among 236 Women from Western Poland
    Oncogene (1997) 15, 1773 ± 1779 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Novel BRCA1 mutations and more frequent intron-20 alteration found among 236 women from Western Poland Krzysztof Sobczak1, Piotr Kozl owski1, Marek Napieral a1, Jakub Czarny1, Marcin WozÂniak1, Mal gorzata Kapus cin ska1,2, Mal gorzataL os ko1, Magdalena Koziczak1, Anna Jasin ska1, Jolanta Powierska1, Ryszard Braczkowski3, Jan Br borowicz4, Dariusz Godlewski2, . e˛ Andrzej Mackiewicz5 and Wl odzimierz Krzyzosiak1 1Laboratory of Cancer Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Z. Noskowskiego 12/14, 61 ± 704 PoznanÂ; 2Cancer Epidemiology and Prevention Union, Wielkopolska Cancer Center, Garbary 15, 61 ± 866 PoznanÂ; 35-th Department of Internal Medicine, Silesian University School of Medicine, Bytom; 4Chair of Oncology, University School of Medical Sciences, La˛kowa 1/2 61-878 PoznanÂ; 5Department of Cancer Immunology, University School of Medical Sciences at Wielkopolska Cancer Center, Garbary 15, 61-866 PoznanÂ, Poland Three dierent novel BRCA1 mutations, ®ve independent most frequently form a favorable genetic background cases of the same 12 bp insertion-duplication in intron-20 for the disease. Also at increased risk are the carriers of and two novel rare BRCA1 sequence variants were one abnormal allele of the ataxia telangiectasia gene identi®ed among 122 Polish women with positive, in most (Swift et al., 1991), the carriers of rare minisatelite cases moderate family history of breast and/or ovarian allele at the HRAS1 locus (Krontiris et al., 1993) and cancer, 80 controls and 34 unselected breast cancer the members of Li Fraumeni families with germline tissue specimens.
    [Show full text]
  • BRE Plays an Essential Role in Preventing Replicative and DNA
    www.nature.com/scientificreports OPEN BRE plays an essential role in preventing replicative and DNA damage-induced premature Received: 08 December 2015 Accepted: 08 March 2016 senescence Published: 22 March 2016 Wenting Shi1, Mei Kuen Tang1, Yao Yao1, Chengcheng Tang1, Yiu Loon Chui2 & Kenneth Ka Ho Lee1 The BRE gene, alias BRCC45, produces a 44 kDa protein that is normally distributed in both cytoplasm and nucleus. In this study, we used adult fibroblasts isolated from wild-type (WT) and BRE knockout (BRE−/−) mice to investigate the functional role of BRE in DNA repair and cellular senescence. We compared WT with BRE−/− fibroblasts at different cell passages and observed that the mutant fibroblasts entered replicative senescence earlier than the WT fibroblasts. With the use of gamma irradiation to induce DNA damage in fibroblasts, the percentage of SA-β-Gal+ cells was significantly higher in BRE−/− fibroblasts compared with WT cells, suggesting that BRE is also associated with DNA damage-induced premature senescence. We also demonstrated that the gamma irradiation induced γ-H2AX foci, a DNA damage marker, persisted significantly longer in BRE−/− fibroblasts than in WT fibroblasts, confirming that the DNA repair process is impaired in the absence of BRE. In addition, the BRCA1-A complex recruitment and homologous recombination (HR)-dependent DNA repair process upon DNA damage were impaired in BRE−/− fibroblasts. Taken together, our results demonstrate a role for BRE in both replicative senescence and DNA damage-induced premature senescence. This can be attributed to BRE being required for BRCA1-A complex-driven HR DNA repair. Cellular senescence is an irreversible physiological process that accompanies abnormal and reduced metabolic activities.
    [Show full text]
  • The Atypical Cyclin-Like Protein Spy1 Overrides P53-Mediated Tumour
    Fifield et al. Breast Cancer Research (2019) 21:140 https://doi.org/10.1186/s13058-019-1211-3 RESEARCH ARTICLE Open Access The atypical cyclin-like protein Spy1 overrides p53-mediated tumour suppression and promotes susceptibility to breast tumourigenesis Bre-Anne Fifield1, Ingrid Qemo1, Evie Kirou1, Robert D. Cardiff2 and Lisa Ann Porter1* Abstract Background: Breast cancer is the most common cancer to affect women and one of the leading causes of cancer- related deaths. Proper regulation of cell cycle checkpoints plays a critical role in preventing the accumulation of deleterious mutations. Perturbations in the expression or activity of mediators of cell cycle progression or checkpoint activation represent important events that may increase susceptibility to the onset of carcinogenesis. The atypical cyclin-like protein Spy1 was isolated in a screen for novel genes that could bypass the DNA damage response. Clinical data demonstrates that protein levels of Spy1 are significantly elevated in ductal and lobular carcinoma of the breast. We hypothesized that elevated Spy1 would override protective cell cycle checkpoints and support the onset of mammary tumourigenesis. Methods: We generated a transgenic mouse model driving expression of Spy1 in the mammary epithelium. Mammary development, growth characteristics and susceptibility to tumourigenesis were studied. In vitro studies were conducted to investigate the relationship between Spy1 and p53. Results: We found that in the presence of wild-type p53, Spy1 protein is held ‘in check’ via protein degradation, representing a novel endogenous mechanism to ensure protected checkpoint control. Regulation of Spy1 by p53 is at the protein level and is mediated in part by Nedd4.
    [Show full text]
  • Tumour Suppressor OTUD3 Induces Growth Inhibition and Apoptosis by Directly Deubiquitinating and Stabilizing P53 in Invasive Breast Carcinoma
    Tumour suppressor OTUD3 induces growth inhibition and apoptosis by directly deubiquitinating and stabilizing p53 in invasive breast carcinoma Qian Pu Shandong University Qilu Hospital Yan-rong Lv Shandong University Qilu Hospital Ke Dong Shandong University Qilu Hospital Wen-wen Geng Shandong University Qilu Hospital Hai-dong Gao ( [email protected] ) Shandong University Qilu Hospital Research article Keywords: OTUD3, p53, deubiquitinating enzymes, invasive breast carcinoma Posted Date: November 4th, 2019 DOI: https://doi.org/10.21203/rs.2.16872/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published on June 22nd, 2020. See the published version at https://doi.org/10.1186/s12885-020-07069-9. Page 1/21 Abstract Background P53 pathway inactivation plays an important role in the process of breast cancer tumourigenesis. Post-translational protein modication abnormalities have been conrmed to be an important mechanism underlying the inactivation of p53. Numerous deubiquitinating enzymes are aberrantly expressed in breast cancer, and a few deubiquitination enzymes are capable of deubiquitinating and stabilizing p53. Here, we report that OTUD3 is a deubiquitylase of p53 in breast carcinoma.Methods The correlation between the mRNA expression of OTUD3, TP53 and PTEN and the prognosis of BC was assessed with the Kaplan-Meier Plotter tool. OTUD3 protein expression in breast carcinoma was examined by immunohistochemistry and western blotting. The relationship among OTUD3, p53, and p21 proteins was analysed. Half-life analysis and ubiquitylation assay were performed to elucidate the molecular mechanism by which OTUD3 stabilizes p53.
    [Show full text]
  • An Integrated Data Analysis Approach to Characterize Genes Highly Expressed in Hepatocellular Carcinoma
    Oncogene (2005) 24, 3737–3747 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma Mohini A Patil1,6, Mei-Sze Chua2,6, Kuang-Hung Pan3,6, Richard Lin3, Chih-Jian Lih3, Siu-Tim Cheung4, Coral Ho1,RuiLi2, Sheung-Tat Fan4, Stanley N Cohen3, Xin Chen1,5 and Samuel So2 1Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143, USA; 2Department of Surgery and Asian Liver Center, Stanford University, Stanford, CA 94305, USA; 3Department of Genetics, Stanford University, Stanford, CA 94305, USA; 4Department of Surgery and Center for the Study of Liver Disease, University of Hong Kong, Hong Kong, China; 5Liver Center, University of California, San Francisco, CA 94143, USA Hepatocellular carcinoma (HCC) is one of the major cancer deaths worldwide (Parkin, 2001; Parkin et al., causes of cancer deaths worldwide. New diagnostic and 2001). Epidemiological and molecular genetic studies therapeutic options are needed for more effective and early have demonstrated that the development of HCC spans detection and treatment of this malignancy. We identified several decades, often starting with hepatitis B virus 703 genes that are highly expressed in HCC using DNA (HBV) or hepatitis C virus (HCV) infections. Chronic microarrays, and further characterized them in order to carriers of HBV or HCV are at much higher risk of uncover novel tumor markers, oncogenes, and therapeutic developing HCC, especially when infection has been targets for HCC. Using Gene Ontology annotations, genes accompanied by liver cirrhosis (El-Serag, H., 2001; El- with functions related to cell proliferation and cell cycle, Serag, H.B., 2002).
    [Show full text]
  • Breast Cancer
    Breast cancer Description Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare. In its early stages, breast cancer usually does not cause pain and may exhibit no noticeable symptoms. As the cancer progresses, signs and symptoms can include a lump or thickening in or near the breast; a change in the size or shape of the breast; nipple discharge, tenderness, or retraction (turning inward); and skin irritation, dimpling, redness, or scaliness. However, these changes can occur as part of many different conditions. Having one or more of these symptoms does not mean that a person definitely has breast cancer. In some cases, cancerous cells can invade surrounding breast tissue. In these cases, the condition is known as invasive breast cancer. Sometimes, tumors spread to other parts of the body. If breast cancer spreads, cancerous cells most often appear in the bones, liver, lungs, or brain. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers. A small percentage of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations.
    [Show full text]
  • Anti-BRE Monoclonal Antibody, Clone FQS22969 (DCABH-6454) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-BRE monoclonal antibody, clone FQS22969 (DCABH-6454) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Product Overview Rabbit monoclonal to BRCC45 Antigen Description Component of the BRCA1-A complex, a complex that specifically recognizes Lys-63-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes Lys-63-linked ubiquitin on histones H2A and H2AX. In the BRCA1-A complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer. Probably also plays a role as a component of the BRISC complex, a multiprotein complex that specifically cleaves Lys-63-linked ubiquitin. May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF-alpha signaling through its interactions with TNFRSF1A; however these effects may be indirect. Isotype IgG Source/Host Rabbit Species Reactivity Mouse, Rat, Human Clone FQS22969 Purity Tissue culture supernatant Conjugate Unconjugated Applications WB, ICC/IF, IHC-P Positive Control fetal brain, Human placenta, HeLa, and Raji lysates; Human lung adenocarcinoma tissue; Human pancreas tissue; MCF-7 cells Format Liquid Size 100 μl 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved Preservative None Storage Store at +4°C short term (1-2 weeks).
    [Show full text]
  • P53/P73 Protein Network in Colorectal Cancer and Other Human Malignancies
    cancers Review p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies Andela¯ Horvat †, Ana Tadijan † , Ignacija Vlaši´c † and Neda Slade * Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruder¯ Boškovi´cInstitute, Bijeniˇcka54, 10000 Zagreb, Croatia; [email protected] (A.H.); [email protected] (A.T.); [email protected] (I.V.) * Correspondence: [email protected] † Contributed equally. Simple Summary: The p53 family of proteins comprises p53, p63, and p73, which share high structural and functional similarity. The two distinct promoters of each locus, the alternative splicing, and the alternative translation initiation sites enable the generation of numerous isoforms with different protein-interacting domains and distinct activities. The co-expressed p53/p73 isoforms have significant but distinct roles in carcinogenesis. Their activity is frequently impaired in human tumors including colorectal carcinoma due to dysregulated expression and a dominant-negative effect accomplished by some isoforms and p53 mutants. The interactions between isoforms are particularly important to understand the onset of tumor formation, progression, and therapeutic response. The understanding of the p53/p73 network can contribute to the development of new targeted therapies. Abstract: The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Citation: Horvat, A.; Tadijan, A.; Each family member possesses two promoters and alternative translation initiation sites, and they Vlaši´c,I.; Slade, N. p53/p73 Protein undergo alternative splicing, generating multiple isoforms.
    [Show full text]