DOCSLIB.ORG

Targeting NRAS-Mutant Cancers with the Selective STK19 Kinase

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Targeting NRAS-Mutant Cancers with the Selective STK19 Kinase Published OnlineFirst March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-2604 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Targeting NRAS-Mutant Cancers with the Selective STK19 Kinase Inhibitor Chelidonine A C Ling Qian1,2, Kun Chen1,2, Changhong Wang3, Zhen Chen1,2, Zhiqiang Meng1,2, and Peng Wang1,2 ABSTRACT ◥ Purpose: Oncogenic mutations in NRAS promote tumori- cell extracts. The antitumor potency of chelidonine was investi- genesis. Although novel anti-NRAS inhibitors are urgently gated in vitro and in vivo using a panel of NRAS-mutant and needed for the treatment of cancer, the protein is generally NRAS wild-type cancer cells. considered “undruggable” and no effective therapies have yet Results: Chelidonine was identified as a potent and selective reached the clinic. STK19 kinase was recently reported to be a inhibitor of STK19 kinase activity. In vitro, chelidonine treatment novel activator of NRAS and a potential therapeutic target for inhibited NRAS signaling, leading to reduced cell proliferation NRAS-mutant melanomas. Here, we describe a new pharma- and induction of apoptosis in a panel of NRAS-mutant cancer cologic inhibitor of STK19 kinase for the treatment of NRAS- cell lines, including melanoma, liver, lung, and gastric cancer. mutant cancers. In vivo, chelidonine suppressed the growth of NRAS-driven Experimental Design: The STK19 kinase inhibitor was iden- tumor cells in nude mice while exhibiting minimal toxicity. tified from a natural compound library using a luminescent Conclusions: Chelidonine suppresses NRAS-mutant cancer phosphorylation assay as the primary screen followed by verifi- cell growth and could have utility as a new treatment for such cation with an in vitro kinase assay and immunoblotting of treated malignancies. Introduction patients with NRAS-mutant melanoma in a phase III trial; however, binimetinib is still in clinical development (14, 15). The RAS family of small GTPases (HRAS, NRAS, and KRAS) are Recent work demonstrated that the functionally uncharacterized binary molecular switches that transition between an active GTP- serine/threonine kinase STK19 is a novel activator of NRAS (16, 17). bound state and an inactive GDP-bound state (1–4). Stimulation of STK19 phosphorylates NRAS at the evolutionarily conserved residue many cell surface receptors activates membrane-bound RAS proteins serine 89 (S89), which enhances binding between NRAS and its and its downstream signaling pathways, including RAF–MEK–ERK effector proteins, activates downstream signaling pathways, and and PI3K–AKT, which culminate in the promotion of cell growth induces malignant transformation of melanocytes (17). Crossing of and suppression of cell death (5, 6). Aberrant RAS activity due to NRAS Q61R transgenic mice with mice harboring melanocyte-specific oncogenic mutations is frequently associated with the promotion of expression of STK19 or the gain-of-function mutant STK19 D89N tumorigenesis (7, 8); indeed, RAS mutations are present in 20%–30% enhances melanoma formation, confirming the ability of STK19 to of all human cancers (8, 9). Melanoma is characterized by gain-of- stimulate NRAS signaling (17, 18). These observations suggest that function hotspot mutations in NRAS at glutamate 61 (Q61; refs. 10, 11), selective STK19 inhibitors could provide urgently needed therapeutic including arginine, lysine, and leucine mutations (Q61R, Q61K, options to suppress the growth of NRAS-mutant tumors. and Q61L), which are present in approximately 30% of melanomas. Chelidonine is one of the most abundant bioactive isoquinoline These mutations result in a constitutively GTP-bound active confor- alkaloids in extracts of the plant Chelidonium majus, which is also mation of NRAS that drives the malignant transformation of known as the greater celandine (Papaveraceae) and is widely distrib- melanocytes (10–13). However, pharmacologic targeting of mutant uted throughout Europe and Asia (19). Crude extracts of Chelidonium NRAS proteins and the downstream signaling pathways has been majus and purified chelidonine have both been shown to possess challenging. Some drugs with the potential to treat NRAS-mutant antitumor properties, including inhibition of cell proliferation, poten- cancers have been developed, such as the MEK inhibitor binimetinib, tiation of apoptosis, and suppression of cell migration and invasion, in which showed some improvement in progression-free survival of cell lines from such diverse cancers as uveal melanoma, head and neck cancer, gastric carcinoma, liver cancer, and breast cancer (20–24). For 1 example, chelidonine potentiates apoptosis in the HCT116 (KRAS Department of Integrative Oncology, Fudan University Shanghai Cancer Center, k Shanghai, China. 2Department of Oncology, Shanghai Medical College, Fudan G13D) human colon cancer cell line by inhibiting the NF- B signaling University, Shanghai, China. 3Institute of Chinese Materia Medica, Shanghai pathway (25), and it suppresses the migration and invasion of MDA- University of Traditional Chinese Medicine, Shanghai, China. MB-231 (KRAS G13D) human breast cancer cells by inhibiting – –a Note: Supplementary data for this article are available at Clinical Cancer formation of the integrin-linked kinase PINCH -parvin com- Research Online (http://clincancerres.aacrjournals.org/). plex (26). However, the precise mechanisms of action of chelidonine L. Qian and K. Chen contributed equally to this article. and its direct targets in cancer cells remain unclear, greatly hindering its translation to the clinic. Corresponding Author: Peng Wang, Fudan University Shanghai Cancer Center, In this study, we screened a natural compound library using a 270 Dong An Road, Shanghai 200032, China. Phone: 8621-6417-5590; Fax: 8621- – fi 6443-7657; E-mail: [email protected] phosphorylation assay based approach and identi ed chelidonine as a potent and selective inhibitor of STK19. Using biochemical and Clin Cancer Res 2020;26:3408–19 cellular assays, we show that chelidonine is an ATP-competitive doi: 10.1158/1078-0432.CCR-19-2604 inhibitor of STK19 activity and blocks proliferation and induces Ó2020 American Association for Cancer Research. apoptosis in a panel of NRAS-mutant cancer cell lines via inhibition AACRJournals.org | 3408 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 10, 2020; DOI: 10.1158/1078-0432.CCR-19-2604 Chelidonine for NRAS-Mutant Cancer Treatment irradiated diet and sterilized water. The mice were monitored daily for Translational Relevance signs related to their health status and distress. Oncogenic mutations in NRAS promote tumorigenesis, and For toxicity profiling of chelidonine, C57BL/6J mice were injected novel anti-NRAS inhibitors are urgently needed for cancer treat- intraperitoneally with vehicle [normal saline containing 5% (w/v) ment. STK19 kinase was recently identified as a novel activator of Kolliphor HS 15; Sigma] or chelidonine (10 or 20 mg/kg in vehicle) NRAS and a potential therapeutic target for NRAS-mutant mel- once daily and body weights were measured daily. After 21 days, the anomas. In this study, we identified chelidonine, a natural com- mice were euthanized, and blood and organs were collected. Serum pound, as a potent and selective inhibitor of STK19 kinase activity. aspartate and alanine aminotransferase (AST and ALT) activity was Chelidonine effectively inhibited proliferation and induced apo- measured using Assay Kits (Abcam) according to the manufacturer's ptosis in a panel of cancer cells harboring NRAS mutations. instructions. The organs were processed by fixing in 4% paraformal- Chelidonine also suppressed NRAS-driven tumor growth in a dehyde and embedding in paraffin using standard protocols. Tissues mouse model while displaying minimal toxicity. These data indi- were cut into 5-mm thick sections, stained with hematoxylin and eosin cate that chelidonine can suppress the growth of NRAS-mutant (H&E), and observed by light microscopy. cancer cells and could represent a novel option for the treatment of The pharmacokinetic profile of chelidonine was analyzed in mice such malignancies. injected intraperitoneally with chelidonine at 10 mg/kg. Chelidonine concentrations in mouse plasma were measured using an ultra-high performance LC/MS-MS (UHPLC/MS-MS) method established for this study. of pathways downstream of NRAS, including RAF–MEK–ERK and In vivo xenograft experiments were performed as described previ- PI3K–AKT. Similarly, chelidonine impaired cancer cell growth in vivo ously (27). Briefly, 2  106 SK-MEL-2 (NRAS Q61R), WM1366 while having minimal toxicity. Our results suggest that pharmacologic (NRAS Q61L), or SK-MEL-28 (NRAS-WT) cells were mixed with inhibition of STK19 by chelidonine may provide a novel option for Matrigel (1:1) and injected subcutaneously into the left flanks of targeting NRAS-mutant cancers. 8-week-old female nude mice. Tumor size was measured every 3 days with calipers, and tumor volumes were calculated using the following formula: length  width2  0.5. When the tumor volume reached Materials and Methods approximately 200 mm3, mice were injected with vehicle or chelido- Cell lines nine (10 or 20 mg/kg, i.p.) once daily. On the indicated days, the mice SK-MEL-2, SK-MEL-28, SK-MEL-31, HepG2, Hep3B, NCI-H446, were euthanized, and melanoma xenografts were excised, weighed, and SW-1271, HCT116, and MDA-MB-231 cell lines were purchased from processed for further analysis. ATCC; WM2032, WM3406, and WM1366
Load more

Recommended publications
  • Core Lab Brochure
    CHOOSE THE MOST TRUSTED LONG-READ TECHNOLOGY FOR YOUR CORE Sequence with Confidence The Sequel® II and IIe Systems are powered by Single Molecule, Real-Time (SMRT®) Sequencing, a technology proven to produce highly accurate long reads, known as HiFi reads, for sequencing data you and your customers can trust. SMRT SEQUENCING IS SMART BUSINESS HiFi Reads: PacBio is the only sequencing technology to offer highly accurate long reads. Because HiFi reads are extremely accurate, downstream analysis is simplified and streamlined, requiring less compute time than the error-prone long reads of other technologies. High Throughput: The Sequel II and IIe Systems have high data yields on robust, highly automated platforms to increase productivity and reduce project costs. Efficient and Easy-To-Use Workflows: Our end-to-end solutions feature library preparation in <3 hours and many push- button analysis workflows, so you can run projects quickly and easily. Support: All of our products are backed by a global team of scientists, bioinformaticians, and engineers who stand ready to provide you with outstanding service. OUTSTANDING PERFORMANCE AND RELIABILITY 99% of runs on the Sequel II System completed successfully Sequel II Systems provide reliable performance with the total bases produced by the PacBio fleet steadily increasing, and 99% of runs completed successfully. “In our experience, the Sequel II System was essentially production-ready right out of the box. We have used it for a range of applications and sample types — from human genome sequencing to metagenome and microbiome profiling to non-model plant and animal genomes — and results have been very good.” — Luke Tallon, Director of the Genomics Resource Center at Maryland Genomics pacb.com/Sequel SMRT SEQUENCING APPLICATIONS – EFFICIENT AND COST EFFECTIVE The Sequel II and IIe Systems support a wide range of applications, each adding unique value to a sequencing study.
    [Show full text]
  • Detection of Driver Mutations in FFPE Samples from Patients with Verified Malignant Melanoma
    Neoplasma 2019; 66(1): 33–38 33 doi:10.4149/neo_2018_180115N31 Detection of driver mutations in FFPE samples from patients with verified malignant melanoma B. MALICHEROVA1,2,#,*, T. BURJANIVOVA1,2,#, E. MINARIKOVA3, I. KASUBOVA1,2, T. PECOVA3, M. BOBROVSKA4, I. HOMOLA5, Z. LASABOVA1,2,6, L. PLANK1,2,4 1Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Commenius University in Bratislava (JFM CU), Slovakia; 2Division of Oncology JFM CU, Martin, Slovakia; 3Clinic of Dermatovenerology, Jessenius Faculty of Medicine and University Hospital in Martin, Martin, Slovakia; 4Department of Pathological Anatomy, Jessenius Faculty of Medicine and University Hospital in Martin, Martin, Slovakia; 5Depart- ment of Plastic Surgery, Jessenius Faculty of Medicine and University Hospital in Martin, Martin, Slovakia; 6Department of Molecular Biology, JFM CU, Martin Slovakia *Correspondence: [email protected] #Contributed equally to this work. Received January 15, 2018 / Accepted April 24, 2018 Malignant melanoma is an oncological disease characterized by etiologic heterogeneity and it has increasing incidence and mortality in the Slovak Republic. While it is treated surgically in combination with chemotherapy, targeted therapy, and immunotherapy, malignant melanomas can ulcerate and are susceptible to infections. These are highly aggressive cancers with metastasis, and recent studies have shown the presence of mutations in RAC1, PPP6C and STK19 genes in melanoma patients. Mutations in these genes are driver mutations; important in oncogenesis and providing selective advantage to tumor cells. The aim of our study is to establish a method to detect driver mutations in formalin-fixed, paraffin embedded (FFPE) tissue DNA. We applied Sanger sequencing to detect driver somatic mutations in RAC1, PPP6C, STK19 and BRAF genes in patients with malignant melanoma.
    [Show full text]
  • Next-Generation Sequencing
    Tinhofer et al. Radiation Oncology (2015) 10:183 DOI 10.1186/s13014-015-0481-x REVIEW Open Access Next-generation sequencing: hype and hope for development of personalized radiation therapy? Ingeborg Tinhofer1,2*, Franziska Niehr1,2, Robert Konschak1,2, Sandra Liebs2, Matthias Munz3, Albrecht Stenzinger4, Wilko Weichert4,5, Ulrich Keilholz6 and Volker Budach1,2 Abstract The introduction of next-generation sequencing (NGS) in the field of cancer research has boosted worldwide efforts of genome-wide personalized oncology aiming at identifying predictive biomarkers and novel actionable targets. Despite considerable progress in understanding the molecular biology of distinct cancer entities by the use of this revolutionary technology and despite contemporaneous innovations in drug development, translation of NGS findings into improved concepts for cancer treatment remains a challenge. The aim of this article is to describe shortly the NGS platforms for DNA sequencing and in more detail key achievements and unresolved hurdles. A special focus will be given on potential clinical applications of this innovative technique in the field of radiation oncology. Introduction and Wong et al. [11]. We will instead focus on key achieve- Recent technological advances in DNA sequencing with ments in cancer genetics and potential clinical applications of greater speed and resolution at lower costs has provided this innovative technique in the field of radiation oncology. new insights in cancer genetics. The next-generation se- quencing (NGS) technology is tremendously facilitating the in-depth genome-wide search for genetic alterations The advantages of NGS which might significantly contribute to aggressive and/or Next-generation sequencing has rapidly been evolv- treatment-resistant phenotypes of cancers, thereby es- ing within the last decade [10].
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Profiling Data
    Compound Name DiscoveRx Gene Symbol Entrez Gene Percent Compound Symbol Control Concentration (nM) JNK-IN-8 AAK1 AAK1 69 1000 JNK-IN-8 ABL1(E255K)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317I)-nonphosphorylated ABL1 87 1000 JNK-IN-8 ABL1(F317I)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317L)-nonphosphorylated ABL1 65 1000 JNK-IN-8 ABL1(F317L)-phosphorylated ABL1 61 1000 JNK-IN-8 ABL1(H396P)-nonphosphorylated ABL1 42 1000 JNK-IN-8 ABL1(H396P)-phosphorylated ABL1 60 1000 JNK-IN-8 ABL1(M351T)-phosphorylated ABL1 81 1000 JNK-IN-8 ABL1(Q252H)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(Q252H)-phosphorylated ABL1 56 1000 JNK-IN-8 ABL1(T315I)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(T315I)-phosphorylated ABL1 92 1000 JNK-IN-8 ABL1(Y253F)-phosphorylated ABL1 71 1000 JNK-IN-8 ABL1-nonphosphorylated ABL1 97 1000 JNK-IN-8 ABL1-phosphorylated ABL1 100 1000 JNK-IN-8 ABL2 ABL2 97 1000 JNK-IN-8 ACVR1 ACVR1 100 1000 JNK-IN-8 ACVR1B ACVR1B 88 1000 JNK-IN-8 ACVR2A ACVR2A 100 1000 JNK-IN-8 ACVR2B ACVR2B 100 1000 JNK-IN-8 ACVRL1 ACVRL1 96 1000 JNK-IN-8 ADCK3 CABC1 100 1000 JNK-IN-8 ADCK4 ADCK4 93 1000 JNK-IN-8 AKT1 AKT1 100 1000 JNK-IN-8 AKT2 AKT2 100 1000 JNK-IN-8 AKT3 AKT3 100 1000 JNK-IN-8 ALK ALK 85 1000 JNK-IN-8 AMPK-alpha1 PRKAA1 100 1000 JNK-IN-8 AMPK-alpha2 PRKAA2 84 1000 JNK-IN-8 ANKK1 ANKK1 75 1000 JNK-IN-8 ARK5 NUAK1 100 1000 JNK-IN-8 ASK1 MAP3K5 100 1000 JNK-IN-8 ASK2 MAP3K6 93 1000 JNK-IN-8 AURKA AURKA 100 1000 JNK-IN-8 AURKA AURKA 84 1000 JNK-IN-8 AURKB AURKB 83 1000 JNK-IN-8 AURKB AURKB 96 1000 JNK-IN-8 AURKC AURKC 95 1000 JNK-IN-8
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases Andrea I
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.01.020206; this version posted April 2, 2020. The copyright holder has placed this preprint (which was not certified by peer review) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share, reuse, remix, or adapt this material for any purpose without crediting the original authors. Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases Andrea I. Krahn, Carrow Wells, David H. Drewry, Lenore K. Beitel, Thomas M. Durcan, Alison D. Axtman* ABSTRACT: Kinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anti-cancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases. KEYWORDS: kinase, neurodegeneration,
    [Show full text]
  • Lineage-Specific Programming Target Genes Defines Potential for Th1 Temporal Induction Pattern of STAT4
    Downloaded from http://www.jimmunol.org/ by guest on October 1, 2021 is online at: average * The Journal of Immunology published online 26 August 2009 from submission to initial decision 4 weeks from acceptance to publication J Immunol http://www.jimmunol.org/content/early/2009/08/26/jimmuno l.0901411 Temporal Induction Pattern of STAT4 Target Genes Defines Potential for Th1 Lineage-Specific Programming Seth R. Good, Vivian T. Thieu, Anubhav N. Mathur, Qing Yu, Gretta L. Stritesky, Norman Yeh, John T. O'Malley, Narayanan B. Perumal and Mark H. Kaplan Submit online. Every submission reviewed by practicing scientists ? is published twice each month by http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://www.jimmunol.org/content/suppl/2009/08/26/jimmunol.090141 1.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* • Why • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of October 1, 2021. Published August 26, 2009, doi:10.4049/jimmunol.0901411 The Journal of Immunology Temporal Induction Pattern of STAT4 Target Genes Defines Potential for Th1 Lineage-Specific Programming1 Seth R. Good,2* Vivian T. Thieu,2† Anubhav N. Mathur,† Qing Yu,† Gretta L.
    [Show full text]
  • Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association Between BMI and Adult-Onset Non- Atopic
    Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non- Atopic Asthma Ayoung Jeong 1,2, Medea Imboden 1,2, Akram Ghantous 3, Alexei Novoloaca 3, Anne-Elie Carsin 4,5,6, Manolis Kogevinas 4,5,6, Christian Schindler 1,2, Gianfranco Lovison 7, Zdenko Herceg 3, Cyrille Cuenin 3, Roel Vermeulen 8, Deborah Jarvis 9, André F. S. Amaral 9, Florian Kronenberg 10, Paolo Vineis 11,12 and Nicole Probst-Hensch 1,2,* 1 Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; [email protected] (A.J.); [email protected] (M.I.); [email protected] (C.S.) 2 Department of Public Health, University of Basel, 4001 Basel, Switzerland 3 International Agency for Research on Cancer, 69372 Lyon, France; [email protected] (A.G.); [email protected] (A.N.); [email protected] (Z.H.); [email protected] (C.C.) 4 ISGlobal, Barcelona Institute for Global Health, 08003 Barcelona, Spain; [email protected] (A.-E.C.); [email protected] (M.K.) 5 Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain 6 CIBER Epidemiología y Salud Pública (CIBERESP), 08005 Barcelona, Spain 7 Department of Economics, Business and Statistics, University of Palermo, 90128 Palermo, Italy; [email protected] 8 Environmental Epidemiology Division, Utrecht University, Institute for Risk Assessment Sciences, 3584CM Utrecht, Netherlands; [email protected] 9 Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College, SW3 6LR London, UK; [email protected] (D.J.); [email protected] (A.F.S.A.) 10 Division of Genetic Epidemiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 11 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK; [email protected] 12 Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy * Correspondence: [email protected]; Tel.: +41-61-284-8378 Int.
    [Show full text]
  • Review of the Molecular Genetics of Basal Cell Carcinoma; Inherited Susceptibility, Somatic Mutations, and Targeted Therapeutics
    cancers Review Review of the Molecular Genetics of Basal Cell Carcinoma; Inherited Susceptibility, Somatic Mutations, and Targeted Therapeutics James M. Kilgour , Justin L. Jia and Kavita Y. Sarin * Department of Dermatology, Stanford University School of Medcine, Stanford, CA 94305, USA; [email protected] (J.M.K.); [email protected] (J.L.J.) * Correspondence: [email protected] Simple Summary: Basal cell carcinoma is the most common human cancer worldwide. The molec- ular basis of BCC involves an interplay of inherited genetic susceptibility and somatic mutations, commonly induced by exposure to UV radiation. In this review, we outline the currently known germline and somatic mutations implicated in the pathogenesis of BCC with particular attention paid toward affected molecular pathways. We also discuss polymorphisms and associated phenotypic traits in addition to active areas of BCC research. We finally provide a brief overview of existing non-surgical treatments and emerging targeted therapeutics for BCC such as Hedgehog pathway inhibitors, immune modulators, and histone deacetylase inhibitors. Abstract: Basal cell carcinoma (BCC) is a significant public health concern, with more than 3 million cases occurring each year in the United States, and with an increasing incidence. The molecular basis of BCC is complex, involving an interplay of inherited genetic susceptibility, including single Citation: Kilgour, J.M.; Jia, J.L.; Sarin, nucleotide polymorphisms and genetic syndromes, and sporadic somatic mutations, often induced K.Y. Review of the Molecular Genetics of Basal Cell Carcinoma; by carcinogenic exposure to UV radiation. This review outlines the currently known germline and Inherited Susceptibility, Somatic somatic mutations implicated in the pathogenesis of BCC, including the key molecular pathways Mutations, and Targeted affected by these mutations, which drive oncogenesis.
    [Show full text]
  • R Graphics Output
    TNF signaling pathway all genes sink node genes ● ●● ●● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ●●● ● ●● ● ● ● ● ● ● ●● ●● ● ● ● ● ●● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ●● ● ● ●● ●●● ●●● ●●● ● ● ● ●●● ● ●●● ● maximum = 3 maximum = 2 2 1 s> 10 0 <log −1 −2 2 1 x a m s 0 10 log −1 −2 group 1 group 2 group 3 group 4 group 5 group 6 group 7 group 8 TNF_signaling_pathway genes with data CASP10 CCL2 CCL5 CCL20 CASP7 FADD CXCL1 CXCL1 CXCL1 CASP3 CASP8 CXCL5 CXCL10 CX3CL1 CSF1 CSF2 BIRC2 ITCH CFLAR FAS IL18R1 JAG1 MAP3K5 IL1B IL6 IL15 LIF LTA TAB1 MAP2K7 MAPK8 FOS BCL3 NFKBIA SOCS3 TNFAIP3 TRAF1 TRAF2 MAP3K7 TNF TNFRSF1A TRADD RIPK1 MAP2K3 MAPK14 CEBPB MAP3K8 NFKB1 RPS6KA4 CREB3 BAG4 MAP3K14 MAP2K1 MAPK1 FOS JUN JUNB MMP3 MMP9 MMP14 IKBKB NFKBIA CHUK EDN1 VEGFC IKBKG NFKB1 NOD2 RIPK1 RIPK3 MLKL PGAM5 ICAM1 SELE VCAM1 DNM1L PGAM5 PTGS2 PIK3CA AKT3 NFKB1 MAP3K14 CHUK NFKBIA TRAF1 LTA TNFRSF1B TRAF2 BIRC2 RIPK1 MAP2K3 MAPK14 TRAF3 DAB2IP MAPK8 JUN IRF1 IFNB1 TNF_signaling_pathway sink nodes CASP10 CCL2 CCL5 CCL20 CASP7 FADD CXCL1 CXCL1 CXCL1 CASP3 CASP8 CXCL5 CXCL10 CX3CL1 CSF1 CSF2 BIRC2 ITCH CFLAR FAS IL18R1 JAG1 MAP3K5 IL1B IL6 IL15 LIF LTA TAB1 MAP2K7 MAPK8 FOS BCL3 NFKBIA SOCS3 TNFAIP3 TRAF1 TRAF2 MAP3K7 TNF TNFRSF1A TRADD
    [Show full text]
  • The Mtor Substrate S6 Kinase 1 (S6K1)
    The Journal of Neuroscience, July 26, 2017 • 37(30):7079–7095 • 7079 Cellular/Molecular The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury X Hassan Al-Ali,1,2,3* Ying Ding,5,6* Tatiana Slepak,1* XWei Wu,5 Yan Sun,5,7 Yania Martinez,1 Xiao-Ming Xu,5 Vance P. Lemmon,1,3 and XJohn L. Bixby1,3,4 1Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida 33136, 2Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, 3Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, 4Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, 5Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, 6Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China, and 7Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China Themammaliantargetofrapamycin(mTOR)positivelyregulatesaxongrowthinthemammaliancentralnervoussystem(CNS).Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demon- strate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold.
    [Show full text]