Multidrug Transporter MRP4/ABCC4 As a Key Determinant of Pancreatic
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The Role of Nuclear Lamin B1 in Cell Proliferation and Senescence
Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press The role of nuclear lamin B1 in cell proliferation and senescence Takeshi Shimi,1 Veronika Butin-Israeli,1 Stephen A. Adam,1 Robert B. Hamanaka,2 Anne E. Goldman,1 Catherine A. Lucas,1 Dale K. Shumaker,1 Steven T. Kosak,1 Navdeep S. Chandel,2 and Robert D. Goldman1,3 1Department of Cell and Molecular Biology, 2Department of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA Nuclear lamin B1 (LB1) is a major structural component of the nucleus that appears to be involved in the regulation of many nuclear functions. The results of this study demonstrate that LB1 expression in WI-38 cells decreases during cellular senescence. Premature senescence induced by oncogenic Ras also decreases LB1 expression through a retinoblastoma protein (pRb)-dependent mechanism. Silencing the expression of LB1 slows cell proliferation and induces premature senescence in WI-38 cells. The effects of LB1 silencing on proliferation require the activation of p53, but not pRb. However, the induction of premature senescence requires both p53 and pRb. The proliferation defects induced by silencing LB1 are accompanied by a p53-dependent reduction in mitochondrial reactive oxygen species (ROS), which can be rescued by growth under hypoxic conditions. In contrast to the effects of LB1 silencing, overexpression of LB1 increases the proliferation rate and delays the onset of senescence of WI-38 cells. This overexpression eventually leads to cell cycle arrest at the G1/S boundary. -
Role of RUNX1 in Aberrant Retinal Angiogenesis Jonathan D
Page 1 of 25 Diabetes Identification of RUNX1 as a mediator of aberrant retinal angiogenesis Short Title: Role of RUNX1 in aberrant retinal angiogenesis Jonathan D. Lam,†1 Daniel J. Oh,†1 Lindsay L. Wong,1 Dhanesh Amarnani,1 Cindy Park- Windhol,1 Angie V. Sanchez,1 Jonathan Cardona-Velez,1,2 Declan McGuone,3 Anat O. Stemmer- Rachamimov,3 Dean Eliott,4 Diane R. Bielenberg,5 Tave van Zyl,4 Lishuang Shen,1 Xiaowu Gai,6 Patricia A. D’Amore*,1,7 Leo A. Kim*,1,4 Joseph F. Arboleda-Velasquez*1 Author affiliations: 1Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114 2Universidad Pontificia Bolivariana, Medellin, Colombia, #68- a, Cq. 1 #68305, Medellín, Antioquia, Colombia 3C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 4Retina Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles St., Boston, MA 02114 5Vascular Biology Program, Boston Children’s Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 6Center for Personalized Medicine, Children’s Hospital Los Angeles, Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, USA 7Department of Pathology, Harvard Medical School, 25 Shattuck St., Boston, MA 02115 Corresponding authors: Joseph F. Arboleda-Velasquez: [email protected] Ph: (617) 912-2517 Leo Kim: [email protected] Ph: (617) 912-2562 Patricia D’Amore: [email protected] Ph: (617) 912-2559 Fax: (617) 912-0128 20 Staniford St. Boston MA, 02114 † These authors contributed equally to this manuscript Word Count: 1905 Tables and Figures: 4 Diabetes Publish Ahead of Print, published online April 11, 2017 Diabetes Page 2 of 25 Abstract Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population, and affects those with type 1 and type 2 diabetes mellitus. -
Bcl-2–Modifying Factor Induces Renal Proximal Tubular Cell Apoptosis in Diabetic Mice Garnet J
ORIGINAL ARTICLE Bcl-2–Modifying Factor Induces Renal Proximal Tubular Cell Apoptosis in Diabetic Mice Garnet J. Lau,1 Nicolas Godin,1 Hasna Maachi,1 Chao-Sheng Lo,1 Shyh-Jong Wu,1 Jian-Xin Zhu,1 Marie-Luise Brezniceanu,1 Isabelle Chénier,1 Joelle Fragasso-Marquis,1 Jean-Baptiste Lattouf,1 Jean Ethier,1 Janos G. Filep,2 Julie R. Ingelfinger,3 Viji Nair,4 Matthias Kretzler,4 Clemens D. Cohen,5 Shao-Ling Zhang,1 and John S.D. Chan1 – This study investigated the mechanisms underlying tubular apopto- than glomerular pathology (2 5). For example, examination sis in diabetes by identifying proapoptotic genes that are differen- of nephrons from proteinuric diabetic patients shows that tially upregulated by reactive oxygen species in renal proximal 71% of glomeruli display glomerulotubular junction abnor- tubular cells (RPTCs) in models of diabetes. Total RNAs isolated malities and 8–17% of glomeruli are atubular glomeruli (6,7). from renal proximal tubules (RPTs) of 20-week-old heterozygous The mechanisms underlying tubular atrophy are incom- db/m+, db/db,anddb/db catalase (CAT)-transgenic (Tg) mice were pletely delineated. Studies have shown that high glucose used for DNA chip microarray analysis. Real-time quantitative PCR (HG) concentrations are associated with increased reactive assays, immunohistochemistry, and mice rendered diabetic with oxygen species (ROS) production, which inhibits proximal streptozotocin were used to validate the proapoptotic gene expres- – sion in RPTs. Cultured rat RPTCs were used to confirm the apoptotic tubular function and induces apoptosis (8 10). Apoptosis activity and regulation of proapoptotic gene expression. Addition- has been detected in renal proximal tubular cells (RPTCs) ally, studies in kidney tissues from patients with and without diabe- of diabetic mice (11,12) and rats (13,14) as well as in RPTCs teswereusedtoconfirm enhanced proapoptotic gene expression in of diabetic patients (15–17), suggesting that tubular apo- RPTs. -
Estimation of Non-Null SNP Effect Size Distributions Enables the Detection
bioRxiv preprint doi: https://doi.org/10.1101/597484; this version posted May 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 1 Estimation of Non-null SNP Effect Size Distributions Enables 2 the Detection of Enriched Genes Underlying Complex Traits 3 1,2 1,2 2-4 4 Wei Cheng , Sohini Ramachandran y, and Lorin Crawford y 5 1 Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, 6 USA 7 2 Center for Computational Molecular Biology, Brown University, Providence, RI, USA 8 3 Department of Biostatistics, Brown University, Providence, RI, USA 9 4 Center for Statistical Sciences, Brown University, Providence, RI, USA 10 Corresponding E-mail: [email protected]; lorin [email protected] y 11 Abstract 12 Traditional univariate genome-wide association studies generate false positives and negatives due to 13 difficulties distinguishing associated variants from variants with spurious nonzero effects that do not 14 directly influence the trait. Recent efforts have been directed at identifying genes or signaling pathways 15 enriched for mutations in quantitative traits or case-control studies, but these can be computationally 16 costly and hampered by strict model assumptions. Here, we present gene-", a new approach for identifying 17 statistical associations between sets of variants and quantitative traits. Our key insight is that enrichment 18 studies on the gene-level are improved when we reformulate the genome-wide SNP-level null hypothesis 19 to identify spurious small-to-intermediate SNP effects and classify them as non-causal. -
Supplementary Figures and Tables
SUPPLEMENTARY DATA Supplementary Figure 1. Isolation and culture of endothelial cells from surgical specimens of FVM. (A) Representative pre-surgical fundus photograph of a right eye exhibiting a FVM encroaching on the optic nerve (dashed line) causing tractional retinal detachment with blot hemorrhages throughout retina (arrow heads). (B) Magnetic beads (arrows) allow for separation and culturing of enriched cell populations from surgical specimens (scale bar = 100 μm). (C) Cultures of isolated cells stained positively for CD31 representing a successfully isolated enriched population (scale bar = 40 μm). ©2017 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1035/-/DC1 SUPPLEMENTARY DATA Supplementary Figure 2. Efficient siRNA knockdown of RUNX1 expression and function demonstrated by qRT-PCR, Western Blot, and scratch assay. (A) RUNX1 siRNA induced a 60% reduction of RUNX1 expression measured by qRT-PCR 48 hrs post-transfection whereas expression of RUNX2 and RUNX3, the two other mammalian RUNX orthologues, showed no significant changes, indicating specificity of our siRNA. Functional inhibition of Runx1 signaling was demonstrated by a 330% increase in insulin-like growth factor binding protein-3 (IGFBP3) RNA expression level, a known target of RUNX1 inhibition. Western blot demonstrated similar reduction in protein levels. (B) siRNA- 2’s effect on RUNX1 was validated by qRT-PCR and western blot, demonstrating a similar reduction in both RNA and protein. Scratch assay demonstrates functional inhibition of RUNX1 by siRNA-2. ns: not significant, * p < 0.05, *** p < 0.001 ©2017 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1035/-/DC1 SUPPLEMENTARY DATA Supplementary Table 1. -
Arsenic Trioxide-Mediated Suppression of Mir-182-5P Is Associated with Potent Anti-Oxidant Effects Through Up-Regulation of SESN2
www.impactjournals.com/oncotarget/www.oncotarget.com Oncotarget, 2018,Oncotarget, Vol. 9, (No.Advance 22), Publicationspp: 16028-16042 2018 Research Paper Arsenic trioxide-mediated suppression of miR-182-5p is associated with potent anti-oxidant effects through up-regulation of SESN2 Liang-Ting Lin1,10,*, Shin-Yi Liu2,*, Jyh-Der Leu3,4,*, Chun-Yuan Chang1, Shih-Hwa Chiou5,6,7, Te-Chang Lee7,8 and Yi-Jang Lee1,9 1Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan 2Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan 3Division of Radiation Oncology, Taipei City Hospital Ren Ai Branch, Taipei, Taiwan 4Institute of Neuroscience, National Chengchi University, Taipei, Taiwan 5Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan 6Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 7Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan 8Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 9Biophotonics and Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, Taiwan 10Current address: Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong *These authors have contributed equally to this work Correspondence to: Te-Chang Lee, email: [email protected] Yi-Jang Lee, email: [email protected] Keywords: arsenic trioxide; sestrin 2; miR-182; oxidative stress; anti-oxidant effect Received: April 12, 2017 Accepted: February 24, 2018 Published: March 23, 2018 Copyright: Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. -
Quantitative Evaluation of Drug Resistance Profile of Cells Expressing Wild-Type Or Genetic Polymorphic Variants of the Human ABC Transporter ABCC4
Article Quantitative Evaluation of Drug Resistance Profile of Cells Expressing Wild-Type or Genetic Polymorphic Variants of the Human ABC Transporter ABCC4 Megumi Tsukamoto 1, Shiori Sato 2, Kazuhiro Satake 1, Mizuki Miyake 1 and Hiroshi Nakagawa 2,* 1 Department of Applied Biological Chemistry, Graduate School of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai 487-8501, Japan; [email protected] (M.T.); [email protected] (K.S.); [email protected] (M.M.) 2 Department of Applied Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-568-51-9606; Fax: +81-568-52-6594 Received: 14 April 2017; Accepted: 26 June 2017; Published: 4 July 2017 Abstract: Broad-spectrum resistance in cancer cells is often caused by the overexpression of ABC transporters; which varies across individuals because of genetic single-nucleotide polymorphisms (SNPs). In the present study; we focused on human ABCC4 and established cells expressing the wild-type (WT) or SNP variants of human ABCC4 using the Flp-In™ system (Invitrogen, Life Technologies Corp, Carlsbad, CA, USA) based on Flp recombinase-mediated transfection to quantitatively evaluate the effects of nonsynonymous SNPs on the drug resistance profiles of cells. The mRNA levels of the cells expressing each ABCC4 variant were comparable. 3-(4,5-Dimethyl-2- thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay clearly indicated that the EC50 values of azathioprine against cells expressing ABCC4 (WT) were 1.4–1.7-fold higher than those against cells expressing SNP variants of ABCC4 (M184K; N297S; K304N or E757K). -
Genomic and Transcriptome Analysis Revealing an Oncogenic Functional Module in Meningiomas
Neurosurg Focus 35 (6):E3, 2013 ©AANS, 2013 Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas XIAO CHANG, PH.D.,1 LINGLING SHI, PH.D.,2 FAN GAO, PH.D.,1 JONATHAN RUssIN, M.D.,3 LIYUN ZENG, PH.D.,1 SHUHAN HE, B.S.,3 THOMAS C. CHEN, M.D.,3 STEVEN L. GIANNOTTA, M.D.,3 DANIEL J. WEISENBERGER, PH.D.,4 GAbrIEL ZADA, M.D.,3 KAI WANG, PH.D.,1,5,6 AND WIllIAM J. MAck, M.D.1,3 1Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California; 2GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China; 3Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California; 4USC Epigenome Center, Keck School of Medicine, University of Southern California, Los Angeles, California; 5Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, California; and 6Division of Bioinformatics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California Object. Meningiomas are among the most common primary adult brain tumors. Although typically benign, roughly 2%–5% display malignant pathological features. The key molecular pathways involved in malignant trans- formation remain to be determined. Methods. Illumina expression microarrays were used to assess gene expression levels, and Illumina single- nucleotide polymorphism arrays were used to identify copy number variants in benign, atypical, and malignant me- ningiomas (19 tumors, including 4 malignant ones). The authors also reanalyzed 2 expression data sets generated on Affymetrix microarrays (n = 68, including 6 malignant ones; n = 56, including 3 malignant ones). -
Interindividual Differences in the Expression of ATP-Binding
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2018/02/02/dmd.117.079061.DC1 1521-009X/46/5/628–635$35.00 https://doi.org/10.1124/dmd.117.079061 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:628–635, May 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Special Section on Transporters in Drug Disposition and Pharmacokinetic Prediction Interindividual Differences in the Expression of ATP-Binding Cassette and Solute Carrier Family Transporters in Human Skin: DNA Methylation Regulates Transcriptional Activity of the Human ABCC3 Gene s Tomoki Takechi, Takeshi Hirota, Tatsuya Sakai, Natsumi Maeda, Daisuke Kobayashi, and Ichiro Ieiri Downloaded from Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (T.T., T.H., T.S., N.M., I.I.); Drug Development Research Laboratories, Kyoto R&D Center, Maruho Co., Ltd., Kyoto, Japan (T.T.); and Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (D.K.) Received October 19, 2017; accepted January 30, 2018 dmd.aspetjournals.org ABSTRACT The identification of drug transporters expressed in human skin and levels. ABCC3 expression levels negatively correlated with the methylation interindividual differences in gene expression is important for understanding status of the CpG island (CGI) located approximately 10 kilobase pairs the role of drug transporters in human skin. In the present study, we upstream of ABCC3 (Rs: 20.323, P < 0.05). The reporter gene assay revealed evaluated the expression of ATP-binding cassette (ABC) and solute carrier a significant increase in transcriptional activity in the presence of CGI. -
Regulation of MRP4 Expression by Circhipk3 Via Sponging Mir-124-3P/Mir-4524-5P in Hepatocellular Carcinoma
biomedicines Article Regulation of MRP4 Expression by circHIPK3 via Sponging miR-124-3p/miR-4524-5p in Hepatocellular Carcinoma Haihong Hu †, Yu Wang †, Zhiyuan Qin, Wen Sun, Yanhong Chen, Jiaqi Wang, Yingying Wang, Jing Nie, Lu Chen, Sheng Cai, Lushan Yu * and Su Zeng * Cancer Center of Zhejiang University, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; [email protected] (H.H.); [email protected] (Y.W.); [email protected] (Z.Q.); [email protected] (W.S.); [email protected] (Y.C.); [email protected] (J.W.); [email protected] (Y.W.); [email protected] (J.N.); [email protected] (L.C.); [email protected] (S.C.) * Correspondence: [email protected] (L.Y.); [email protected] (S.Z.); Tel.: +86-571-8820-8407 (L.Y.); +86-571-8820-8405 (S.Z.) † These authors contributed equally to this work. Abstract: Multidrug resistance-associated protein 4 (MRP4), a member of the adenosine triphosphate (ATP) binding cassette transporter family, pumps various molecules out of the cell and is involved in cell communication and drug distribution. Several studies have reported the role of miRNAs in downregulating the expression of MRP4. However, regulation of MRP4 by circular RNA (circRNA) Citation: Hu, H.; Wang, Y.; Qin, Z.; is yet to be elucidated. In this study, MRP4 was significantly upregulated in hepatocellular carcinoma Sun, W.; Chen, Y.; Wang, J.; Wang, Y.; (HCC) tissues compared to the adjacent noncancerous tissues. -
Noncoding Rnas As Novel Pancreatic Cancer Targets
NONCODING RNAS AS NOVEL PANCREATIC CANCER TARGETS by Amy Makler A Thesis Submitted to the Faculty of The Charles E. Schmidt College of Science In Partial Fulfillment of the Requirements for the Degree of Master of Science Florida Atlantic University Boca Raton, FL August 2018 Copyright 2018 by Amy Makler ii ACKNOWLEDGEMENTS I would first like to thank Dr. Narayanan for his continuous support, constant encouragement, and his gentle, but sometimes critical, guidance throughout the past two years of my master’s education. His faith in my abilities and his belief in my future success ensured I continue down this path of research. Working in Dr. Narayanan’s lab has truly been an unforgettable experience as well as a critical step in my future endeavors. I would also like to extend my gratitude to my committee members, Dr. Binninger and Dr. Jia, for their support and suggestions regarding my thesis. Their recommendations added a fresh perspective that enriched our initial hypothesis. They have been indispensable as members of my committee, and I thank them for their contributions. My parents have been integral to my successes in life and their support throughout my education has been crucial. They taught me to push through difficulties and encouraged me to pursue my interests. Thank you, mom and dad! I would like to thank my boyfriend, Joshua Disatham, for his assistance in ensuring my writing maintained a logical progression and flow as well as his unwavering support. He was my rock when the stress grew unbearable and his encouraging words kept me pushing along. -
Contribution of Abcc4-Mediated Gastric Transport to the Absorption and Efficacy of Dasatinib
Published OnlineFirst June 21, 2013; DOI: 10.1158/1078-0432.CCR-13-0980 Clinical Cancer Cancer Therapy: Preclinical Research Contribution of Abcc4-Mediated Gastric Transport to the Absorption and Efficacy of Dasatinib Brian D. Furmanski1, Shuiying Hu1, Ken-ichi Fujita1, Lie Li1, Alice A. Gibson1, Laura J. Janke2, Richard T. Williams3, John D. Schuetz1, Alex Sparreboom1, and Sharyn D. Baker1 Abstract Purpose: Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties. Experimental Design: Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wild-type and Abcc4-null mice. þ The influence of Abcc4 deficiency on dasatinib efficacy was evaluated in a model of Ph acute lymphoblastic leukemia by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(À/À) pre-B cells. Results: Dasatinib accumulation was significantly changed in cells overexpressing ABCC4 or Abcc4 compared with control cells (P < 0.001). Deficiency of Abcc4 in vivo was associated with a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of intravenous dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was impaired by Abcc4 deficiency (P < 0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared with wild-type mice (P ¼ 0.048).