DOCSLIB.ORG

Research Article Overexpression of FRAT1 Is Associated with Malignant Phenotype and Poor Prognosis in Human Gliomas

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Research Article Overexpression of FRAT1 Is Associated with Malignant Phenotype and Poor Prognosis in Human Gliomas Hindawi Publishing Corporation Disease Markers Volume 2015, Article ID 289750, 8 pages http://dx.doi.org/10.1155/2015/289750 Research Article Overexpression of FRAT1 Is Associated with Malignant Phenotype and Poor Prognosis in Human Gliomas Geng Guo,1,2 Cheng-liang Zhong,3,4 Yang Liu,5 Xing-gang Mao,6 Zheng Zhang,7 Ji Jin,8 Jing Liu,2 Liu Yang,9 Jin-ming Mao,9 Yu-hong Guo,2 and Yuan-li Zhao1 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China 2DepartmentofNeurosurgery,TheFirstHospital,ShanxiMedicalUniversity,Taiyuan,Shanxi030001,China 3GCP Center, The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300192, China 4Postdoctoral Programme, China Academy of Chinese Medical Sciences, Beijing 100700, China 5Department of Neurosurgery, The Third Hospital of Mianyang, Mianyang, Sichuan 621000, China 6Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China 7Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China 8Shanxi Medical University, Taiyuan, Shanxi 030001, China 9Department of Neurology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China Correspondence should be addressed to Geng Guo; [email protected] and Yuan-li Zhao; [email protected] Received 23 January 2015; Accepted 20 March 2015 Academic Editor: Vincent Sapin Copyright © 2015 Geng Guo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Glioma is the most common malignancy of the central nervous system. Approximately 40 percent of intracranial tumors are diagnosed as gliomas. Difficulties in treatment are associated closely with the malignant phenotype, which is characterized by excessive proliferation, relentless invasion, and angiogenesis. Although the comprehensive treatment level of brain glioma is continuously progressing, the outcome of this malignancy has not been improved drastically. Therefore, the identification of new biomarkers for diagnosis and therapy of this malignancy is of significant scientific and clinical value. FRAT1 is a positive regulator of the Wnt/-catenin signaling pathway and is overexpressed in many human tumors. In the present study, we investigated the expression status of FRAT1 in 68 patients with human gliomas and its correlation with the pathologic grade, proliferation, invasion, angiogenesis, and prognostic significance. These findings suggest that FRAT1 may be an important factor in the tumorigenesis and progression of glioma and could be explored as a potential biomarker for pathological diagnosis, an indicator for prognosis, and a target for biological therapy of malignancy. 1. Introduction despite having undergone surgical treatment combined with radiotherapy and chemotherapy [2]. Therefore, the identifi- Glioma is the most common malignancy of the central cation of new biomarkers for diagnosis and therapy of this nervous system. Approximately 40 percent of intracranial malignancy is of significant scientific and clinical value. tumors are diagnosed as gliomas [1]. Difficulties in treatment The FRAT1 (frequently rearranged in advanced T-cell areassociatedcloselywiththemalignantphenotype,whichis lymphomas-1) gene, located on human chromosome 10q24.1 characterized by excessive proliferation, relentless invasion, [3], encodes a 29 kDa protein comprising 279 amino acids. and angiogenesis. Although the comprehensive treatment FRAT1isapositiveregulatoroftheWnt/-catenin signaling level of brain glioma is continuously progressing, the out- pathway [4–6] and is overexpressed in many human tumors come of this malignancy has not been improved drastically. [7–11]. Recently, we demonstrated that FRAT1 expression For example, patients with the most malignant histopatho- is elevated in gliomas [12, 13] and that its expression is logic subtype, glioblastoma (GBM), carry the worst progno- correlated with pathologic grade, proliferation, and apoptosis sis, with a median survival period of less than 12 months, in astrocytomas [13]. The expression of FRAT1 is considered 2 Disease Markers to be crucial for the maintenance of the malignant cellular phenotype. However, little is known about the contribution of FRAT1 expression to the prognosis of glioma. In the present study, we investigated the expression status of FRAT1 in 68 patients with human gliomas and its correlation with the pathologic grade, proliferation, invasion, angiogenesis, and prognostic significance. These results may have important implications in both predicting the clinical prognosis and understanding the biology of these tumors. 2. Materials and Methods 2.1. Tumor Specimens. Sixty-eight patients with gliomas were included in this retrospective study. All of the cases were surgically treated at the Neurosurgical Department of the Xijing Hospital affiliated to the Fourth Military Medical University from June 2007 to August 2009. The patients included 35 males and 29 females ranging in age from 6 to 76 years (45.6 ± 17.7,mean± standard deviation (SD)). All tumor tissues were obtained from the initial surgery prior to chemotherapy or radiation therapy. The extents of resection (gross total (greater than 90% resected) or subtotal (60% to 90% resected)) were documented on the basis of the surgeon’s intraoperative impression with postoperative radiographic confirmation of the absence or presence of residual disease. The extent of resection was greater than 60% for all patients in the study. Histologic subtypes and pathologic grades of tumors were quantified according to the revised World Health Organization (WHO) criteria for the central nervous system [1] as follows: 10 cases with Grade I, all pilocytic gliomas; 19 cases with Grade II, including 16 diffuse gliomas, 2 oligodendrogliomas, and 1 protoplasmic glioma; 16 cases with Grade III, including 12 anaplastic gliomas and 4 anaplastic oligodendrogliomas; and 23 cases with Grade IV, all glioblastomas. The pathologic grades of all samples were confirmed independently by two pathologists. Five samples of slightly impaired brain tissue fragments from volunteers with cerebral trauma were used as control. Twenty-three patients with glioblastoma were treated with surgery, radio- therapy, and adjuvant chemotherapy. They were followed up every 2 months for at least 24 months posttreatment. This study was approved by the Institutional Review Board of the Xijing Hospital of the Fourth Military Medical University, Xi’an, China. All participants provided written informed 4 Disease Markers Table 1: Measurements of FRAT1 IRS, Pi, Ii, and MVD in gliomas. Glioma tissues FRAT1 IRS Pi % Ii % MVD Grade I 10 1.30 ± 1.77 12.62 ± 11.24 9.18 ± 12.03 30.36 ± 11.69 Grade II 19 2.63 ± 2.91 23.66 ± 13.69 19.84 ± 15.66 51.08 ± 15.27 Grade III 16 4.50 ± 3.76 35.19 ± 16.08 26.80 ± 18.05 73.81 ± 24.52 Grade IV 23 6.70 ± 3.89 48.23 ± 21.05 39.91 ± 19.12 90.14 ± 29.28 Total 68 4.25 ± 3.86a 33.06 ± 20.93a 26.70 ± 19.93a 66.59 ± 31.05a a < 0.001 as compared among Grades I to IV of brain gliomas (by ANOVA). IRS, immunoreactivity score; Pi, proliferative index; Ii, invasive index; MVD, microvessel density. Table 2: IRS, Pi, Ii, and MVD in FRAT1-positive and FRAT1-negative groups of gliomas. All gliomas % (range) FRAT1-positive % FRAT1-negative % Pi 33.06 ± 20.93 (0.8 to 85.3) 45.59 ± 16.78% 14.03 ± 8.51% = 10.21 < 0.001 Ii 26.70 ± 19.3 (0 to 69.0) 36.72 ± 18.29% 11.49 ± 10.51% = 7.21 < 0.001 MVD 66.59 ± 31.05 (14 to 145) 75.10 ± 31.58 53.68 ± 25.75 = 2.94 = 0.0045 Pi, proliferative index; Ii, invasive index; MVD, microvessel density. Grade I Grade II Grade III Grade IV Disease Markers 5 100 12 11 90 10 80 9 70 8 60 7 6 50 5 40 FRAT1 IRS FRAT1 4 30 3 Proliferative index (%) Proliferative 20 2 1 10 0 0 IIIIIIIV IIIIIIIV Pathologic grade Pathologic grade (a) (b) 100 150 140 90 130 80 120 110 70 100 60 90 80 50 70 40 60 50 30 Invasive index (%) Invasive Microvessel density Microvessel 40 20 30 20 10 10 0 0 IIIIIIIV IIIIIIIV Pathologic grade Pathologic grade (c) (d) 6 Disease Markers 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 Invasive index (%) Invasive Proliferative index (%) Proliferative 20 20 10 10 0 0 0 123456 7 8 9 10 11 12 0 123456 7 8 9 10 11 12 FRAT1 IRS FRAT1 IRS (a) (b) 150 140 130 120 110 100 90 80 70 60 50 40 Microvessel density Microvessel 30 20 10 0 0 123456 7 8 9 10 11 12 FRAT1 IRS (c) Figure 3: Correlation of the FRAT1 IRS with other malignant activity scores. Scatterplots demonstrate the correlation of the FRAT1 IRS with the Pi, Ii, and MVD in human glioma. A trend line provided in each plot r Disease Markers 7 1.00 approved the final paper. Geng Guo, Cheng-liang Zhong, and Yang Liu contributed equally to this work. 0.75 Acknowledgments 0.50 The authors appreciate Dr. Li-na Wu (Department of Pathol- ogy, The First Hospital, Shanxi Medical University) and Dr. Ya-qin Li (Department of Pathology, Shanxi Dayi Hospital) 0.25 for confirming the pathological diagnosis of all the samples used in this research and helping to perform microscopic Estimated survival probability Estimated analysis.TheyalsothankMeng-naChen,TingLiu,TingLv, 0.00 Xin Lv, and Xin Rong for preparing for this research. This 0 020406081012141618202224 work was supported by the National Natural Science Foun- dation of China (no. 81201991), the Basic Research Program Observation points (month) of Shanxi Province of China (no. 2012021035-5), the Program Survival curve for the Outstanding Innovative Teams of Higher Learning FRAT1: negative Institutions of Shanxi, and the Scientific Research Subject of FRAT1: positive Shanxi Provincial Health Department (no. 201301066). Figure 4: Correlation of FRAT1 positivity with outcome in GBM. Kaplan-Meier survival analysis of GBM patients with FRAT1- References positive or -negative expression.
Load more

Recommended publications
  • Downloaded the “Top Edge” Version
    bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 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 4.0 International license. 1 Drosophila models of pathogenic copy-number variant genes show global and 2 non-neuronal defects during development 3 Short title: Non-neuronal defects of fly homologs of CNV genes 4 Tanzeen Yusuff1,4, Matthew Jensen1,4, Sneha Yennawar1,4, Lucilla Pizzo1, Siddharth 5 Karthikeyan1, Dagny J. Gould1, Avik Sarker1, Yurika Matsui1,2, Janani Iyer1, Zhi-Chun Lai1,2, 6 and Santhosh Girirajan1,3* 7 8 1. Department of Biochemistry and Molecular Biology, Pennsylvania State University, 9 University Park, PA 16802 10 2. Department of Biology, Pennsylvania State University, University Park, PA 16802 11 3. Department of Anthropology, Pennsylvania State University, University Park, PA 16802 12 4 contributed equally to work 13 14 *Correspondence: 15 Santhosh Girirajan, MBBS, PhD 16 205A Life Sciences Building 17 Pennsylvania State University 18 University Park, PA 16802 19 E-mail: [email protected] 20 Phone: 814-865-0674 21 1 bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 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 4.0 International license. 22 ABSTRACT 23 While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non- 24 neuronal phenotypes, functional studies evaluating these regions have focused on the molecular 25 basis of neuronal defects.
    [Show full text]
  • Analysis of the Indacaterol-Regulated Transcriptome in Human Airway
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/04/13/jpet.118.249292.DC1 1521-0103/366/1/220–236$35.00 https://doi.org/10.1124/jpet.118.249292 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:220–236, July 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the s Adverse and Therapeutic Effects of b2-Adrenoceptor Agonists Dong Yan, Omar Hamed, Taruna Joshi,1 Mahmoud M. Mostafa, Kyla C. Jamieson, Radhika Joshi, Robert Newton, and Mark A. Giembycz Departments of Physiology and Pharmacology (D.Y., O.H., T.J., K.C.J., R.J., M.A.G.) and Cell Biology and Anatomy (M.M.M., R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Received March 22, 2018; accepted April 11, 2018 Downloaded from ABSTRACT The contribution of gene expression changes to the adverse and activity, and positive regulation of neutrophil chemotaxis. The therapeutic effects of b2-adrenoceptor agonists in asthma was general enriched GO term extracellular space was also associ- investigated using human airway epithelial cells as a therapeu- ated with indacaterol-induced genes, and many of those, in- tically relevant target. Operational model-fitting established that cluding CRISPLD2, DMBT1, GAS1, and SOCS3, have putative jpet.aspetjournals.org the long-acting b2-adrenoceptor agonists (LABA) indacaterol, anti-inflammatory, antibacterial, and/or antiviral activity. Numer- salmeterol, formoterol, and picumeterol were full agonists on ous indacaterol-regulated genes were also induced or repressed BEAS-2B cells transfected with a cAMP-response element in BEAS-2B cells and human primary bronchial epithelial cells by reporter but differed in efficacy (indacaterol $ formoterol .
    [Show full text]
  • Exploring the Relationship Between Gut Microbiota and Major Depressive Disorders
    E3S Web of Conferences 271, 03055 (2021) https://doi.org/10.1051/e3sconf/202127103055 ICEPE 2021 Exploring the Relationship between Gut Microbiota and Major Depressive Disorders Catherine Tian1 1Shanghai American School, Shanghai, China Abstract. Major Depressive Disorder (MDD) is a psychiatric disorder accompanied with a high rate of suicide, morbidity and mortality. With the symptom of an increasing or decreasing appetite, there is a possibility that MDD may have certain connections with gut microbiota, the colonies of microbes which reside in the human digestive system. In recent years, more and more studies started to demonstrate the links between MDD and gut microbiota from animal disease models and human metabolism studies. However, this relationship is still largely understudied, but it is very innovative since functional dissection of this relationship would furnish a new train of thought for more effective treatment of MDD. In this study, by using multiple genetic analytic tools including Allen Brain Atlas, genetic function analytical tools, and MicrobiomeAnalyst, I explored the genes that shows both expression in the brain and the digestive system to affirm that there is a connection between gut microbiota and the MDD. My approach finally identified 7 MDD genes likely to be associated with gut microbiota, implicating 3 molecular pathways: (1) Wnt Signaling, (2) citric acid cycle in the aerobic respiration, and (3) extracellular exosome signaling. These findings may shed light on new directions to understand the mechanism of MDD, potentially facilitating the development of probiotics for better psychiatric disorder treatment. 1 Introduction 1.1 Major Depressive Disorder Major Depressive Disorder (MDD) is a mood disorder that will affect the mood, behavior and other physical parts.
    [Show full text]
  • The Database of Chromosome Imbalance Regions and Genes
    Lo et al. BMC Cancer 2012, 12:235 http://www.biomedcentral.com/1471-2407/12/235 RESEARCH ARTICLE Open Access The database of chromosome imbalance regions and genes resided in lung cancer from Asian and Caucasian identified by array-comparative genomic hybridization Fang-Yi Lo1, Jer-Wei Chang1, I-Shou Chang2, Yann-Jang Chen3, Han-Shui Hsu4, Shiu-Feng Kathy Huang5, Fang-Yu Tsai2, Shih Sheng Jiang2, Rajani Kanteti6, Suvobroto Nandi6, Ravi Salgia6 and Yi-Ching Wang1* Abstract Background: Cancer-related genes show racial differences. Therefore, identification and characterization of DNA copy number alteration regions in different racial groups helps to dissect the mechanism of tumorigenesis. Methods: Array-comparative genomic hybridization (array-CGH) was analyzed for DNA copy number profile in 40 Asian and 20 Caucasian lung cancer patients. Three methods including MetaCore analysis for disease and pathway correlations, concordance analysis between array-CGH database and the expression array database, and literature search for copy number variation genes were performed to select novel lung cancer candidate genes. Four candidate oncogenes were validated for DNA copy number and mRNA and protein expression by quantitative polymerase chain reaction (qPCR), chromogenic in situ hybridization (CISH), reverse transcriptase-qPCR (RT-qPCR), and immunohistochemistry (IHC) in more patients. Results: We identified 20 chromosomal imbalance regions harboring 459 genes for Caucasian and 17 regions containing 476 genes for Asian lung cancer patients. Seven common chromosomal imbalance regions harboring 117 genes, included gain on 3p13-14, 6p22.1, 9q21.13, 13q14.1, and 17p13.3; and loss on 3p22.2-22.3 and 13q13.3 were found both in Asian and Caucasian patients.
    [Show full text]
  • The Expression Profile of FRAT1 in Human Gliomas
    BRAIN RESEARCH 1320 (2010) 152– 158 available at www.sciencedirect.com www.elsevier.com/locate/brainres Research Report The expression profile of FRAT1 in human gliomas Geng Guoa,1, Xinggang Maoa,1, Peng Wanga,1, Bolin Liua, Xiang Zhanga,⁎, Xiaofan Jianga, Chengliang Zhongb, Junli Huoa, Ji Jinc, Yuzhen Zhuod aDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 15# West Chang Le Road, Xi'an, Shaanxi Province 710032, People's Republic of China bDepartment of Health Statistics, Faculty of Preventative Medicine, Fourth Military Medical University, 17# West Chang Le Road, Xi'an, Shaanxi Province 710032, People's Republic of China cShanxi Medical University, 56# South Xin Jian Road, Taiyuan, Shanxi Province 030001, People's Republic of China dTianjin Institute of Acute Abdomen, Tianjin Nankai Hospital, 122# San Wei Road, Tianjin 300100, People's Republic of China ARTICLE INFO ABSTRACT Article history: FRAT1 was originally characterized as a protein frequently rearranged in advanced T cell Accepted 13 January 2010 lymphoma, which inhibits GSK-3-mediated phosphorylation of β-catenin and positively Available online 21 January 2010 regulates the Wnt signaling pathway. FRAT1 has been identified as a proto-oncogene involved in tumorigenesis. Previous studies have shown that FRAT1 is strikingly Keywords: overexpressed in some human cancers. However, the relationship between FRAT1 and FRAT1 human gliomas is unclear. In this study, we detected the expression of FRAT1 in human β-catenin gliomas by immunohistochemistry, Western blot and RT-PCR. FRAT1 was found to be Glioma specifically expressed in the majority of glioma samples, and their expression levels Immunohistochemistry increased markedly with the increase of WHO grades.
    [Show full text]
  • 1471-2105-8-217.Pdf
    BMC Bioinformatics BioMed Central Software Open Access GenMAPP 2: new features and resources for pathway analysis Nathan Salomonis1,2, Kristina Hanspers1, Alexander C Zambon1, Karen Vranizan1,3, Steven C Lawlor1, Kam D Dahlquist4, Scott W Doniger5, Josh Stuart6, Bruce R Conklin1,2,7,8 and Alexander R Pico*1 Address: 1Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158 USA, 2Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA, 3Functional Genomics Laboratory, University of California, Berkeley, CA 94720 USA, 4Department of Biology, Loyola Marymount University, 1 LMU Drive, MS 8220, Los Angeles, CA 90045 USA, 5Computational Biology Graduate Program, Washington University School of Medicine, St. Louis, MO 63108 USA, 6Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064 USA, 7Department of Medicine, University of California, San Francisco, CA 94143 USA and 8Department of Molecular and Cellular Pharmacology, University of California, San Francisco, CA 94143 USA Email: Nathan Salomonis - [email protected]; Kristina Hanspers - [email protected]; Alexander C Zambon - [email protected]; Karen Vranizan - [email protected]; Steven C Lawlor - [email protected]; Kam D Dahlquist - [email protected]; Scott W Doniger - [email protected]; Josh Stuart - [email protected]; Bruce R Conklin - [email protected]; Alexander R Pico* - [email protected] * Corresponding author Published: 24 June 2007 Received: 16 November 2006 Accepted: 24 June 2007 BMC Bioinformatics 2007, 8:217 doi:10.1186/1471-2105-8-217 This article is available from: http://www.biomedcentral.com/1471-2105/8/217 © 2007 Salomonis et al; licensee BioMed Central Ltd.
    [Show full text]
  • Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and B-Catenin– Independent Targets by Proteomics
    Published OnlineFirst June 3, 2019; DOI: 10.1158/1541-7786.MCR-18-1154 Cancer "-omics" Molecular Cancer Research Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and b-Catenin– Independent Targets by Proteomics Olesja Popow1,2,3,Joao~ A. Paulo2, Michael H. Tatham4, Melanie S. Volk3, Alejandro Rojas-Fernandez5, Nicolas Loyer3, Ian P. Newton3, Jens Januschke3, Kevin M. Haigis1,6, and Inke Nathke€ 3 Abstract Adenomatous Polyposis Coli (APC) is the most frequently tion between endogenous MINK1 and APC and further mutated gene in colorectal cancer. APC negatively regulates confirmed the negative, and b-catenin–independent, regu- the Wnt signaling pathway by promoting the degradation of lation of MINK1 by APC. Increased Mink1/Msn levels were b-catenin, but the extent to which APC exerts Wnt/b-cate- also observed in mouse intestinal tissue and Drosophila nin–independent tumor-suppressive activity is unclear. To follicular cells expressing mutant Apc/APC when compared identify interaction partners and b-catenin–independent with wild-type tissue/cells. Collectively, our results highlight targets of endogenous, full-length APC, we applied label- the extent and importance of Wnt-independent APC func- free and multiplexed tandem mass tag-based mass spec- tions in epithelial biology and disease. trometry. Affinity enrichment-mass spectrometry identified more than 150 previously unidentified APC interaction Implications: The tumor-suppressive function of APC, the partners. Moreover, our global proteomic analysis revealed most frequently mutated gene in colorectal cancer, is mainly that roughly half of the protein expression changes that attributed to its role in b-catenin/Wnt signaling. Our study occur in response to APC loss are independent of b-catenin.
    [Show full text]
  • A Novel Candidate Tumor Suppressor Gene from 10Q24.3
    Oncogene (2001) 20, 6707 ± 6717 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc LAPSER1: a novel candidate tumor suppressor gene from 10q24.3 Yofre Cabeza-Arvelaiz1, Timothy C Thompson2, Jorge L Sepulveda3 and A Craig Chinault*,1 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, TX 77030, USA; 2Department of Urology, Baylor College of Medicine, Houston, Texas, TX 77030, USA; 3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, PA 15261, USA Numerous LOH and mutation analysis studies in Transfer of these portions of each chromosome into dierent tumor tissues, including prostate, indicate that cancer cells has provided further evidence indicating there are multiple tumor suppressor genes (TSGs) that these regions harbor genes that suppress tumor- present within the human chromosome 8p21 ± 22 and igenicity (Ichikawa et al., 1994; Murakami et al., 1996). 10q23 ± 24 regions. Recently, we showed that LZTS1 (or Several candidate prostate cancer genes have been FEZ1), a putative TSG located on 8p22, has the isolated from 8p21 ± 22, including PRLTS (Fujiwara et potential to function as a cell growth modulator. We al., 1995), N33 (MacGrogan et al., 1996), and FEZ1 report here the cloning, gene organization, cDNA (Ishii et al., 1999). The expression of the latter, which sequence characterization and expression analysis of has now been designated as the LZTS1 (leucine zipper, LAPSER1,anLZTS1-related gene. This gene maps putative tumor suppressor 1) gene, has been found to within a subregion of human chromosome 10q24.3 that be altered in many tumors and cell lines including has been reported to be deleted in various cancers, esophageal, breast and prostate (Ishii et al., 1999).
    [Show full text]
  • Detection of H3k4me3 Identifies Neurohiv Signatures, Genomic
    viruses Article Detection of H3K4me3 Identifies NeuroHIV Signatures, Genomic Effects of Methamphetamine and Addiction Pathways in Postmortem HIV+ Brain Specimens that Are Not Amenable to Transcriptome Analysis Liana Basova 1, Alexander Lindsey 1, Anne Marie McGovern 1, Ronald J. Ellis 2 and Maria Cecilia Garibaldi Marcondes 1,* 1 San Diego Biomedical Research Institute, San Diego, CA 92121, USA; [email protected] (L.B.); [email protected] (A.L.); [email protected] (A.M.M.) 2 Departments of Neurosciences and Psychiatry, University of California San Diego, San Diego, CA 92103, USA; [email protected] * Correspondence: [email protected] Abstract: Human postmortem specimens are extremely valuable resources for investigating trans- lational hypotheses. Tissue repositories collect clinically assessed specimens from people with and without HIV, including age, viral load, treatments, substance use patterns and cognitive functions. One challenge is the limited number of specimens suitable for transcriptional studies, mainly due to poor RNA quality resulting from long postmortem intervals. We hypothesized that epigenomic Citation: Basova, L.; Lindsey, A.; signatures would be more stable than RNA for assessing global changes associated with outcomes McGovern, A.M.; Ellis, R.J.; of interest. We found that H3K27Ac or RNA Polymerase (Pol) were not consistently detected by Marcondes, M.C.G. Detection of H3K4me3 Identifies NeuroHIV Chromatin Immunoprecipitation (ChIP), while the enhancer H3K4me3 histone modification was Signatures, Genomic Effects of abundant and stable up to the 72 h postmortem. We tested our ability to use H3K4me3 in human Methamphetamine and Addiction prefrontal cortex from HIV+ individuals meeting criteria for methamphetamine use disorder or not Pathways in Postmortem HIV+ Brain (Meth +/−) which exhibited poor RNA quality and were not suitable for transcriptional profiling.
    [Show full text]
  • Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
    Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein
    [Show full text]
  • Camp Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression
    The Journal of Neuroscience, December 14, 2011 • 31(50):18237–18250 • 18237 Cellular/Molecular cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression Eva Benito,1 Luis M. Valor,1 Maria Jimenez-Minchan,1 Wolfgang Huber,2 and Angel Barco1 1Instituto de Neurociencias de Alicante, Universidad Miguel Herna´ndez/Consejo Superior de Investigaciones Científicas, Sant Joan d’Alacant, 03550 Alicante, Spain, and 2European Molecular Biology Laboratory Heidelberg, Genome Biology Unit, 69117 Heidelberg, Germany Long-lasting forms of neuronal plasticity require de novo gene expression, but relatively little is known about the events that occur genome-wide in response to activity in a neuronal network. Here, we unveil the gene expression programs initiated in mouse hippocam- pal neurons in response to different stimuli and explore the contribution of four prominent plasticity-related transcription factors (CREB, SRF, EGR1, and FOS) to these programs. Our study provides a comprehensive view of the intricate genetic networks and interac- tions elicited by neuronal stimulation identifying hundreds of novel downstream targets, including novel stimulus-associated miRNAs and candidate genes that may be differentially regulated at the exon/promoter level. Our analyses indicate that these four transcription factors impinge on similar biological processes through primarily non-overlapping gene-expression programs. Meta-analysis of the datasets generated in our study and comparison with publicly available transcriptomics data revealed the individual and collective contribution of these transcription factors to different activity-driven genetic programs. In addition, both gain- and loss-of-function experiments support a pivotal role for CREB in membrane-to-nucleus signal transduction in neurons.
    [Show full text]
  • Supplemental Figure Legends
    Supplemental Figure Legends Supplementary Figure S1 Generation and characterization of Frat-knockout mice (A) Frat/GBP orthologues are conserved amongst vertebrate species, including Xenopus (xl) zebrafish (dr), mice (mm), rats (rn) and humans (hs). Whereas lower organisms such as Xenopus and zebrafish contain one Frat/GBP gene, the human genome harbors two and the mouse genome three Frat homologues. mmFrat1 and mmFrat3 are 84% homologous on the protein level, whereas mmFrat1 and mmFrat2 share 68% amino-acid identity. A multiple- species alignment of Frat proteins reveals conserved domains in the N– and C-terminal regions. The IKEA-box, which is required for binding to GSK-3β, is conserved in all Frat family members. (B) Frat2– and Frat3-knockout mice were generated by replacing most of the coding sequence with a targeting cassette existing of a promoterless lacZ-reporter gene, followed by a PGK-promoter driven Hygromycin resistance marker to allow selection of targeted ES cells. Homologous recombination was analyzed by Southern Blot analysis using 3’ flanking probes. For Frat2 probe A allows detection of the shift of an endogenous 12 kb Xba fragment to a 9 kb fragment after homologous recombination; Probe B for Frat3 detects a shift in the endogenous 24 kb EcoRV fragment to an 18 kb knockout fragment after homologous recombination. (C) Since Frat1 and Frat2 are located on chromosome 19 only 15 kb apart in opposite orientations, a separate targeting vector was constructed to generate Frat1/Frat2 double- knockout mice. Frat2 was targeted with a PGK-Puromycin selection cassette in Frat1+/lacZ ES cells. Homologous recombination was verified by Southern Blot analysis.
    [Show full text]