171 results on '"Edward J. Benz"'
Search Results
2. Remembering the Contributions of Professor David J. Weatherall
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Edward J. Benz
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Oncology ,Hematology - Published
- 2023
3. Thalassemia
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Edward J. Benz and Vijay G. Sankaran
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Oncology ,Hematology - Published
- 2023
4. Progress in Cancer Research, Prevention, and Care
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Edward J. Benz, Sharyl J. Nass, Richard L. Schilsky, and Michelle M. Le Beau
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Biomedical Research ,business.industry ,Health Policy ,Mortality rate ,MEDLINE ,Neoplasms therapy ,General Medicine ,History, 20th Century ,030204 cardiovascular system & hematology ,Medical Oncology ,History, 21st Century ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms diagnosis ,Neoplasms ,Cancer research ,Humans ,Medicine ,030212 general & internal medicine ,business ,Health policy - Abstract
NAM at 50: Progress in Cancer Research, Prevention, and Care Cancer-related mortality has been declining steadily. Treatment advances have reduced death rates for some cancers, but most of the redu...
- Published
- 2020
5. Epithelial-specific isoforms of protein 4.1R promote adherens junction assembly in maturing epithelia
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Faye H. Yu, Henry S. Zhang, Shu-Ching Huang, Jia Y. Liang, Jennie Park Ou, Alexander C. Ou, Long V. Vu, Kimberly M. Burnett, and Edward J. Benz
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0301 basic medicine ,Biochemistry ,Madin Darby Canine Kidney Cells ,Adherens junction ,03 medical and health sciences ,Dogs ,Animals ,Humans ,Protein Isoforms ,Spectrin ,Cytoskeleton ,Molecular Biology ,beta Catenin ,Actin ,Binding Sites ,030102 biochemistry & molecular biology ,Tight junction ,Adherens junction assembly ,Chemistry ,Microfilament Proteins ,Membrane Proteins ,Adherens Junctions ,Cell Biology ,Cadherins ,Actin cytoskeleton ,Actins ,Cell biology ,Alternative Splicing ,Cytoskeletal Proteins ,030104 developmental biology ,Catenin ,Calcium ,Carrier Proteins ,Protein Binding - Abstract
Epithelial adherens junctions (AJs) and tight junctions (TJs) undergo disassembly and reassembly during morphogenesis and pathological states. The membrane–cytoskeleton interface plays a crucial role in junctional reorganization. Protein 4.1R (4.1R), expressed as a diverse array of spliceoforms, has been implicated in linking the AJ and TJ complex to the cytoskeleton. However, which specific 4.1 isoform(s) participate and the mechanisms involved in junctional stability or remodeling remain unclear. We now describe a role for epithelial-specific isoforms containing exon 17b and excluding exon 16 4.1R (4.1R(+17b)) in AJs. 4.1R(+17b) is exclusively co-localized with the AJs. 4.1R(+17b) binds to the armadillo repeats 1–2 of β-catenin via its membrane-binding domain. This complex is linked to the actin cytoskeleton via a bispecific interaction with an exon 17b–encoded peptide. Exon 17b peptides also promote fodrin–actin complex formation. Expression of 4.1R(+17b) forms does not disrupt the junctional cytoskeleton and AJs during the steady-state or calcium-dependent AJ reassembly. Overexpression of 4.1R(−17b) forms, which displace the endogenous 4.1R(+17b) forms at the AJs, as well as depletion of the 4.1R(+17b) forms both decrease junctional actin and attenuate the recruitment of spectrin to the AJs and also reduce E-cadherin during the initial junctional formation of the AJ reassembly process. Expressing 4.1R(+17b) forms in depleted cells rescues junctional localization of actin, spectrin, and E-cadherin assembly at the AJs. Together, our results identify a critical role for 4.1R(+17b) forms in AJ assembly and offer additional insights into the spectrin–actin–4.1R-based membrane skeleton as an emerging regulator of epithelial integrity and remodeling.
- Published
- 2020
6. Advancing the Science of Healthcare Service Delivery
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Eric Thrailkill, Debbie Witchey, Troyen A. Brennan, Richard K. Murray, Harry R. Jacobson, Sundeep Khosla, Edward J. Benz, Harry Leider, Uchechukwu K.A. Sampson, Mark E. Frisse, Sharon B. Arnold, Shari M. Ling, Jonathan B. Perlin, Peter A. Briss, Melinda Beeuwkes Buntin, Jim Macrae, Ron G. King, Carrie Wager, Elizabeth A. McGlynn, and Richard Kuntz
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Community and Home Care ,Government ,Epidemiology ,business.industry ,MEDLINE ,Context (language use) ,030204 cardiovascular system & hematology ,Public relations ,Service provider ,03 medical and health sciences ,0302 clinical medicine ,Transformative learning ,General partnership ,Health care ,Agency (sociology) ,Medicine ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business - Abstract
There is a growing gap between available science and evidence and the ability of service providers to deliver high-quality care in a cost-effective way to the entire population. We believe that the chasm between knowledge and action is due to a lack of concerted effort among all organizations that deliver health care services across the life span of patients. Broad participation is needed and necessitates a far more explicit and concerted public-private partnership focused on large-scale transformation. In this context, the National Heart, Lung, and Blood Institute convened a panel made up of leaders of corporate health care entities, including academic health centers, and government agency representatives to inform contemporary strategic partnerships with health care companies. This article provides insights from the meeting on how to execute a transformative innovation research agenda that will foster improvements in health care service delivery by leveraging the translation of biomedical research evidence in real-world settings.
- Published
- 2018
7. Regulated Fox-2 isoform expression mediates protein 4.1R splicing during erythroid differentiation
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Yang, Guang, Huang, Shu-Ching, Wu, Jane Y., and Edward J., Benz, Jr
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- 2008
- Full Text
- View/download PDF
8. Na,K-ATPase Structure
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Edward J. Benz, Robert W. Mercer, and Jay W. Schneider
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chemistry.chemical_classification ,Membrane potential ,Membrane ,chemistry ,ATP hydrolysis ,Biophysics ,Triphosphatase ,Na+/K+-ATPase ,Intracellular ,Transmembrane protein ,Amino acid - Abstract
The Na,K-adenosine triphosphatase (Na,K-ATPase), also known as the sodium pump or sodium-potassium pump, is a membrane-associated enzyme responsible for maintaining the high internal K concentration and low internal Na concentration characteristic of most animal cells. It couples the hydrolysis of ATP to the transport of Na and K across the plasma membrane against their respective electrochemical gradients. For each ATP hydrolyzed the Na,K-ATPase normally expels three Na ions and takes in two K ions. As outlined in Figure 1, the Na,KATPase is fundamental to several diverse cellular functions. These functions include: (a) regulation of cellular volume; (b) maintenance of the high internal K concentration required for several intracellular enzymes; (c) generation of the transmembrane Na gradient necessary for the uphill transport of sugars, amino acids and ions; (d) maintenance of the ion gradients essential for the membrane potential and the excitability of the membrane; and (e) the transport of Na across the epithelia. Generally up to one-third of an animal cell’s energy requirement is consumed in fueling the Na,K-ATPase. In electrically active tissues or tissues involved in salt transport up to 70% of the cell’s total energy requirement may be used by the pump.
- Published
- 2020
9. Protein 4.1R Influences Myogenin Protein Stability and Skeletal Muscle Differentiation
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Anyu Zhou, Henry S. Zhang, Edward J. Benz, Dan T. Nguyen, and Shu-Ching Huang
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0301 basic medicine ,Myoblasts, Skeletal ,Protein degradation ,Biochemistry ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Myosin ,medicine ,Animals ,Myocyte ,Molecular Biology ,Myogenin ,MyoD Protein ,Mice, Knockout ,biology ,Protein Stability ,Myogenesis ,Membrane Proteins ,Skeletal muscle ,Cell Differentiation ,Cell Biology ,musculoskeletal system ,Molecular biology ,Cytoskeletal Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Von Hippel-Lindau Tumor Suppressor Protein ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,Dystrophin ,tissues ,C2C12 - Abstract
Protein 4.1R (4.1R) isoforms are expressed in both cardiac and skeletal muscle. 4.1R is a component of the contractile apparatus. It is also associated with dystrophin at the sarcolemma in skeletal myofibers. However, the expression and function of 4.1R during myogenesis have not been characterized. We now report that 4.1R expression increases during C2C12 myoblast differentiation into myotubes. Depletion of 4.1R impairs skeletal muscle differentiation and is accompanied by a decrease in the levels of myosin heavy and light chains and caveolin-3. Furthermore, the expression of myogenin at the protein, but not mRNA, level is drastically decreased in 4.1R knockdown myocytes. Similar results were obtained using MyoD-induced differentiation of 4.1R−/− mouse embryonic fibroblast cells. von Hippel-Lindau (VHL) protein is known to destabilize myogenin via the ubiquitin-proteasome pathway. We show that 4.1R associates with VHL and, when overexpressed, reverses myogenin ubiquitination and stability. This suggests that 4.1R may influence myogenesis by preventing VHL-mediated myogenin degradation. Together, our results define a novel biological function for 4.1R in muscle differentiation and provide a molecular mechanism by which 4.1R promotes myogenic differentiation.
- Published
- 2016
10. Value, Access, and Cost of Cancer Care Delivery at Academic Cancer Centers
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Joseph C. Alvarnas, Yuman Fong, Julie A. Wolfson, Dennis D. Weisenburger, Stanton L. Gerson, Robert B. Diasio, Edward J. Benz, C. Lyn Fitzgerald, Sharon Stranford, Steven T. Rosen, Maggie Egan, Barbara A. Parker, Elizabeth A. Nardi, Harlan Levine, and Robert W. Carlson
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Value (ethics) ,Medical education ,medicine.medical_specialty ,geography ,Summit ,geography.geographical_feature_category ,business.industry ,media_common.quotation_subject ,Cancer ,Medical Oncology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Work (electrical) ,Neoplasms ,030220 oncology & carcinogenesis ,Family medicine ,medicine ,Humans ,Quality (business) ,030212 general & internal medicine ,business ,Delivery of Health Care ,media_common - Abstract
Key challenges facing the oncology community today include access to appropriate, high quality, patient-centered cancer care; defining and delivering high-value care; and rising costs. The National Comprehensive Cancer Network convened a Work Group composed of NCCN Member Institution cancer center directors and their delegates to examine the challenges of access, high costs, and defining and demonstrating value at the academic cancer centers. The group identified key challenges and possible solutions to addressing these issues. The findings and recommendations of the Work Group were then presented at the Value, Access, and Cost of Cancer Care Policy Summit in September 2015 and multi-stakeholder roundtable panel discussions explored these findings and recommendations along with additional items.
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- 2016
11. Iron‐Loading Anaemia
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Edward J. Benz
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Ineffective erythropoiesis ,medicine.medical_specialty ,biology ,Red Cell ,Thalassemia ,Iron deficiency ,medicine.disease ,medicine.disease_cause ,Endocrinology ,Hepcidin ,hemic and lymphatic diseases ,Internal medicine ,medicine ,biology.protein ,Erythropoiesis ,Transfusion therapy ,Hormone - Abstract
This article outlines the key pathophysiologic factors underlying the three major forms of anaemia that are particularly likely to cause severe iron overload in patients, even without chronic transfusion therapy: the thalassaemia syndromes, sideroblastic anaemias and congenital dyserythropoietic anaemia. These forms of anaemia cause iron overload by impairing erythropoiesis in ways that cause accelerated turnover of developing erythroblasts in the marrow (ineffective erythropoiesis). The increased demand for non-productive proliferation of erythroblasts disrupts the hepcidin-mediated regulation of iron homeostasis. This leads to continued high levels of oral iron absorption despite the fact that iron from the destroyed erythroblasts cannot be excreted. As correction of the underlying illness is often not feasible, management usually focuses on judicious use of blood replacement and iron chelation. Key Concepts Iron is essential for aerobic life because it mediates the ability of oxygen to interact productively with the energy-producing biochemical systems of the organism. Iron is indispensable for haemoglobin and red cell production, and therefore, the oxygen tranportation system of the body. Giving its essentiality for survival, iron stores are jealously protected by the body. Thus, there are no mechanisms for excreting iron, even when iron stores are present in excess amounts. Almost all of the iron in the body is conserved by an intricate recycling mechanism from senescent red cells. Absorption of new iron is intended to replace only the small amount of iron lost daily by bleeding and ell shedding. Iron stores are regulated by controlling uptake from dietary sources. A complex endocrine system regulated by the hormone hepcidin plays the key role. In this regulatory cycle, increased erythroid activity in the marrow is interpreted to be a response to iron deficiency, even if iron stores are normal or high. Iron-overloading anaemias are those in which inefficient production of red cell results in excess iron absorption despite normal or elevated total body iron stores. Ineffective erythropoiesis more severe than that seen in other anaemias is the hallmark of the major iron-loading anaemias: thalassaemia, sideroblastic anaemias and congenital dyserythropietic anaemias. These anaemias are not easily corrected at the mechanistic level so that iron chelation therapy, with or without red cell transfusion support, is usually necessary. Keywords: iron; haemoglobin; haemochromatosis; anaemia; thalassaemia
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- 2015
12. Value of Oncology Pharmacists in the Oncology Health Care Workforce—Reply
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Lisa Kennedy Sheldon, Edward J. Benz, and Lawrence N. Shulman
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Cancer Research ,medicine.medical_specialty ,business.industry ,MEDLINE ,Health care workforce ,Medical Oncology ,Pharmacists ,United States ,Oncology ,Neoplasms ,Pharmaceutical Services ,Family medicine ,Workforce ,medicine ,Humans ,business ,Delivery of Health Care ,Value (mathematics) - Published
- 2020
13. The Future of Cancer Care in the United States—Overcoming Workforce Capacity Limitations
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Edward J. Benz, Lisa Kennedy Sheldon, and Lawrence N. Shulman
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Cancer Research ,Oncology ,Nursing ,business.industry ,Workforce ,MEDLINE ,Medicine ,Cancer ,business ,medicine.disease - Published
- 2020
14. Advancing the Science of Healthcare Service Delivery: The NHLBI Corporate Healthcare Leaders' Panel
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Uchechukwu K A, Sampson, Elizabeth A, McGlynn, Jonathan B, Perlin, Mark E, Frisse, Sharon B, Arnold, Edward J, Benz, Troyen, Brennan, Peter, Briss, Melinda J, Beeuwkes Buntin, Sundeep, Khosla, Ron G, King, Richard, Kuntz, Harry, Leider, Shari M, Ling, Jim, Macrae, Richard, Murray, Eric, Thrailkill, Carrie, Wager, Debbie, Witchey, and Harry R, Jacobson
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Leadership ,Biomedical Research ,Consensus ,Cardiovascular Diseases ,Cardiology ,Humans ,Delivery of Health Care ,United States - Abstract
There is a growing gap between available science and evidence and the ability of service providers to deliver high-quality care in a cost-effective way to the entire population. We believe that the chasm between knowledge and action is due to a lack of concerted effort among all organizations that deliver health care services across the life span of patients. Broad participation is needed and necessitates a far more explicit and concerted public-private partnership focused on large-scale transformation. In this context, the National Heart, Lung, and Blood Institute convened a panel made up of leaders of corporate health care entities, including academic health centers, and government agency representatives to inform contemporary strategic partnerships with health care companies. This article provides insights from the meeting on how to execute a transformative innovation research agenda that will foster improvements in health care service delivery by leveraging the translation of biomedical research evidence in real-world settings.
- Published
- 2018
15. Structural Hemoglobinopathies
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Edward J. Benz
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- 2018
16. Anemias
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Edward J. Benz
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- 2018
17. Sideroblastic Anemias
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Nathan T. Connell and Edward J. Benz
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- 2018
18. Anemias, Red Cells, and the Essential Elements of Red Cell Homeostasis
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Edward J. Benz
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Red Cell ,business.industry ,Medicine ,business ,Homeostasis ,Cell biology - Published
- 2018
19. Preface
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Ronald Hoffman, Edward J. Benz, Leslie E. Silberstein, Helen E. Heslop, Jeffrey I. Weitz, John Anastasi, Mohammed E. Salama, and Syed Abutalib
- Published
- 2018
20. Hemoglobin Variants Associated With Hemolytic Anemia, Altered Oxygen Affinity, and Methemoglobinemias
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Benjamin L. Ebert and Edward J. Benz
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Hemolytic anemia ,medicine.medical_specialty ,biology ,Chemistry ,Haptoglobin ,Hemoglobin variants ,Methemoglobinemia ,medicine.disease ,Oxygen affinity ,Endocrinology ,Hemoglobinopathy ,Internal medicine ,Immunology ,medicine ,biology.protein ,Hemoglobin ,Heinz body - Published
- 2018
21. Anatomy and Physiology of the Gene
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Edward J. Benz, Nancy Berliner, and Andrew J. Wagner
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0301 basic medicine ,Regulation of gene expression ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Evolutionary biology ,030220 oncology & carcinogenesis ,Biology ,Gene - Published
- 2018
22. Contributors
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Omar Abdel-Wahab, Janet L. Abrahm, Sharon Adams, Adeboye H. Adewoye, Carl Allen, Richard F. Ambinder, Claudio Anasetti, John Anastasi, Julia A. Anderson, Joseph H. Antin, Aśok C. Antony, David J. Araten, Philippe Armand, Gillian Armstrong, Scott A. Armstrong, Donald M. Arnold, Andrew S. Artz, Farrukh T. Awan, Trevor P. Baglin, Don M. Benson, Edward J. Benz, Nancy Berliner, Govind Bhagat, Nina Bhardwaj, Ravi Bhatia, Smita Bhatia, Mihir D. Bhatt, Vijaya Raj Bhatt, Menachem Bitan, Craig D. Blinderman, Catherine M. Bollard, Benjamin S. Braun, Malcolm K. Brenner, Gary M. Brittenham, Robert A. Brodsky, Myles Brown, Hal E. Broxmeyer, Kathleen Brummel-Ziedins, Andrew M. Brunner, Francis K. Buadi, Birgit Burkhardt, Melissa Burns, John C. Byrd, Paolo F. Caimi, Michael A. Caligiuri, Michelle Canavan, Alan B. Cantor, Manuel Carcao, Michael C. Carroll, Shannon A. Carty, Jorge J. Castillo, Anthony K.C. Chan, John Chapin, April Chiu, John P. Chute, David B. Clark, Thomas D. Coates, Christopher R. Cogle, Nathan T. Connell, Elizabeth Cooke, Sarah Cooley, Paolo Corradini, Mark A. Creager, Richard J. Creger, Caroline Cromwell, Mark A. Crowther, Melissa M. Cushing, Corey Cutler, Chi V. Dang, Nika N. Danial, Sandeep S. Dave, James A. DeCaprio, Mary C. Dinauer, Shira Dinner, Reyhan Diz-Küçükkaya, Roger Y. Dodd, Michele L. Donato, Kenneth Dorshkind, Gianpietro Dotti, Yigal Dror, Kieron Dunleavy, Christopher C. Dvorak, Benjamin L. Ebert, Michael J. Eck, John W. Eikelboom, Narendranath Epperla, William B. Ershler, William E. Evans, Stefan Faderl, James L.M. Ferrara, Alexandra Hult Filipovich, Martin Fischer, James C. Fredenburgh, Kenneth D. Friedman, Ephraim Fuchs, Stephen J. Fuller, David Gailani, Jacques Galipeau, Patrick G. Gallagher, Karthik A. Ganapathi, Lawrence B. Gardner, Adrian P. Gee, Stanton L. Gerson, Morie A. Gertz, Patricia J. Giardina, Christopher J. Gibson, Karin Golan, Todd R. Golub, Matthew J. Gonzales, Jason Gotlib, Stephen Gottschalk, Marianne A. Grant, Timothy A. Graubert, Xylina T. Gregg, John G. Gribben, Dawn M. Gross, Tanja A. Gruber, Joan Guitart, Sandeep Gurbuxani, Shiri Gur-Cohen, Alejandro Gutierrez, Mehdi Hamadani, Parameswaran N. Hari, John H. Hartwig, Suzanne R. Hayman, Catherine P.M. Hayward, Robert P. Hebbel, Helen E. Heslop, Christopher Hillis, Christopher D. Hillyer, Karin Ho, David M. Hockenbery, Ronald Hoffman, Kerstin E. Hogg, Shernan G. Holtan, Hans-Peter Horny, Yen-Michael S. Hsu, Zachary R. Hunter, James A. Huntington, Camelia Iancu-Rubin, Ali Iqbal, David E. Isenman, Sara J. Israels, Joseph E. Italiano, Elaine S. Jaffe, Iqbal H. Jaffer, Sundar Jagannath, Ulrich Jäger, Nitin Jain, Paula James, Sima Jeha, Michael B. Jordan, Cassandra D. Josephson, Moonjung Jung, Leo Kager, Taku Kambayashi, Jennifer A. Kanakry, Hagop M. Kantarjian, Jason Kaplan, Matthew S. Karafin, Aly Karsan, Randal J. Kaufman, Richard M. Kaufman, Frank G. Keller, Kara M. Kelly, Craig M. Kessler, Nigel S. Key, Alla Keyzner, Alexander G. Khandoga, Arati Khanna-Gupta, Eman Khatib-Massalha, Harvey G. Klein, Birgit Knoechel, Orit Kollet, Barbara A. Konkle, Dimitrios P. Kontoyiannis, John Koreth, Gary A. Koretzky, Dipak Kotecha, Marina Kremyanskaya, Anju Kumari, Timothy M. Kuzel, Ralf Küppers, Martha Q. Lacy, Elana Ladas, Wendy Landier, Kfir Lapid, Tsvee Lapidot, Peter J. Larson, Marcel Levi, Russell E. Lewis, Howard A. Liebman, David Lillicrap, Wendy Lim, Judith C. Lin, Robert Lindblad, Gregory Y.H. Lip, Jane A. Little, Jens G. Lohr, José A. López, Francis W. Luscinskas, Jaroslaw P. Maciejewski, Navneet S. Majhail, Olivier Manches, Robert J. Mandle, Kenneth G. Mann, Catherine S. Manno, Andrea N. Marcogliese, Guglielmo Mariani, Francesco M. Marincola, John Mascarenhas, Steffen Massberg, Rodger P. McEver, Emer McGrath, Matthew S. McKinney, Rohtesh S. Mehta, William C. Mentzer, Giampaolo Merlini, Reid Merryman, Marc Michel, Anna Rita Migliaccio, Jeffrey S. Miller, Martha P. Mims, Traci Heath Mondoro, Paul Moorehead, Luciana R. Muniz, Nikhil C. Munshi, Vesna Najfeld, Lalitha Nayak, Ishac Nazy, Anne T. Neff, Paul M. Ness, Luigi D. Notarangelo, Sarah H. O'Brien, Owen A. O'Connor, Martin O'Donnell, Amanda Olson, Stuart H. Orkin, Menaka Pai, Sung-Yun Pai, Michael Paidas, Sandhya R. Panch, Reena L. Pande, Thalia Papayannopoulou, Rahul Parikh, Effie W. Petersdorf, Shane E. Peterson, Stefania Pittaluga, Doris M. Ponce, Laura Popolo, Josef T. Prchal, Ching-Hon Pui, Pere Puigserver, Janusz Rak, Carlos A. Ramos, Jacob H. Rand, Margaret L. Rand, Dinesh S. Rao, Farhad Ravandi, David J. Rawlings, Pavan Reddy, Mark T. Reding, Andreas Reiter, Lawrence Rice, Matthew J. Riese, Arthur Kim Ritchey, David J. Roberts, Elizabeth Roman, Cliona M. Rooney, Steven T. Rosen, David S. Rosenthal, Marlies P. Rossmann, Antal Rot, Scott D. Rowley, Jeffrey E. Rubnitz, Natalia Rydz, Mohamed E. Salama, Steven Sauk, Yogen Saunthararajah, William Savage, David Scadden, Kristen G. Schaefer, Fred Schiffman, Robert Schneidewend, Stanley L. Schrier, Edward H. Schuchman, Bridget Fowler Scullion, Kathy J. Selvaggi, Keitaro Senoo, Montaser Shaheen, Beth H. Shaz, Samuel A. Shelburne, Elizabeth J. Shpall, Susan B. Shurin, Deborah Siegal, Leslie E. Silberstein, Lev Silberstein, Roy L. Silverstein, Steven R. Sloan, Franklin O. Smith, James W. Smith, Katy Smith, David P. Steensma, Martin H. Steinberg, Wendy Stock, Jill R. Storry, Susan L. Stramer, Ronald G. Strauss, David F. Stroncek, Justin Taylor, Swapna Thota, Steven P. Treon, Anil Tulpule, Roberto Ferro Valdes, Peter Valent, Suresh Vedantham, Gregory M. Vercellotti, Michael R. Verneris, Elliott P. Vichinsky, Ulrich H. von Andrian, Julie M. Vose, Andrew J. Wagner, Ena Wang, Jia-huai Wang, Theodore E. Warkentin, Melissa P. Wasserstein, Ann Webster, Daniel J. Weisdorf, Jeffrey I. Weitz, Connie M. Westhoff, Allison P. Wheeler, Page Widick, James S. Wiley, Basem M. William, David A. Williams, Wyndham H. Wilson, Joanne Wolfe, Lucia R. Wolgast, Deborah Wood, Jennifer Wu, Joachim Yahalom, Donald L. Yee, Anas Younes, Neal S. Young, and Michelle P. Zeller
- Published
- 2018
23. Pathobiology of the Human Erythrocyte and Its Hemoglobins
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Edward J. Benz, Adeboye H. Adewoye, Benjamin L. Ebert, and Martin H. Steinberg
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Biochemistry ,Chemistry ,Erythropoiesis ,Bohr effect ,Oxygen affinity - Published
- 2018
24. Dedication
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Ronald Hoffman, Edward J. Benz, Leslie E. Silberstein, Helen E. Heslop, Jeffrey I. Weitz, John Anastasi, Mohamed E. Salama, and Syed Ali Abutalib
- Published
- 2018
25. The Jeremiah Metzger Lecture Cancer in the Twenty-First Century: An Inside View from an Outsider
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Edward J, Benz
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Biomedical Research ,Gene Expression Regulation ,Neoplasms ,Mutation ,Humans ,Molecular Targeted Therapy ,Articles ,Precision Medicine - Abstract
Cancer is not a single disease. The term refers to literally hundreds of illnesses sharing common features: inappropriate proliferation of imperfectly differentiated cell types, invasion of nearby vital structures, and spread to distant sites (metastasis). Invasiveness and metastasis distinguish cancers from benign tumors such as fibroids and meningiomas. Yet, each type is distinct, possessed of defining morphologic, histologic, biochemical, and genomic features that have allowed oncologists to develop a nosology that guides diagnosis and therapy. Cancer is thus a complex collection of disorders. That complexity is increasing exponentially as modern technologies allow us to dissect each form in ever greater detail. The notion of curing cancer with a “magic bullet” like the polio vaccine is no more realistic than using the same wrench to fix a bicycle, a car, and an airliner just because they are all vehicles.
- Published
- 2017
26. Protein 4.1R Exon 16 3′ Splice Site Activation Requires Coordination among TIA1, Pcbp1, and RBM39 during Terminal Erythropoiesis
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Edward J. Benz, Faye H. Yu, Dan T. Nguyen, Henry S. Zhang, Jennie Park Ou, Shu-Ching Huang, Alexander C. Ou, Ellen McMahon, and Brian Yu
- Subjects
0301 basic medicine ,Spliceosome ,TIA1 ,Biology ,Poly(A)-Binding Proteins ,Heterogeneous-Nuclear Ribonucleoproteins ,03 medical and health sciences ,Exon ,Mice ,Cell Line, Tumor ,Animals ,Humans ,snRNP ,Spectrin ,Erythropoiesis ,Molecular Biology ,Splice site mutation ,Binding Sites ,Alternative splicing ,Membrane Proteins ,Nuclear Proteins ,RNA-Binding Proteins ,Cell Biology ,Phosphoproteins ,Ribonucleoproteins, Small Nuclear ,Splicing Factor U2AF ,Cell biology ,T-Cell Intracellular Antigen-1 ,DNA-Binding Proteins ,Alternative Splicing ,Cytoskeletal Proteins ,030104 developmental biology ,HEK293 Cells ,RNA splicing ,Cancer research ,Spliceosomes ,RNA Splicing Factors ,Research Article ,HeLa Cells ,Protein Binding - Abstract
Exon 16 of protein 4.1R encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability. Its expression during erythroid differentiation is regulated by alternative pre-mRNA splicing. A UUUUCCCCCC motif situated between the branch point and the 3' splice site is crucial for inclusion. We show that the UUUU region and the last three C residues in this motif are necessary for the binding of splicing factors TIA1 and Pcbp1 and that these proteins appear to act in a collaborative manner to enhance exon 16 inclusion. This element also activates an internal exon when placed in a corresponding intronic position in a heterologous reporter. The impact of these two factors is further enhanced by high levels of RBM39, whose expression rises during erythroid differentiation as exon 16 inclusion increases. TIA1 and Pcbp1 associate in a complex containing RBM39, which interacts with U2AF65 and SF3b155 and promotes U2 snRNP recruitment to the branch point. Our results provide a mechanism for exon 16 3' splice site activation in which a coordinated effort among TIA1, Pcbp1, and RBM39 stabilizes or increases U2 snRNP recruitment, enhances spliceosome A complex formation, and facilitates exon definition through RBM39-mediated splicing regulation.
- Published
- 2017
27. Accelerating the Science of SCD Therapies—Is a Cure Possible?
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Edward J. Benz, Traci Heath Mondoro, and Gary H. Gibbons
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Internal medicine ,Genetic enhancement ,medicine ,MEDLINE ,General Medicine ,Hematopoietic stem cell transplantation ,medicine.disease ,business ,Sickle cell anemia - Published
- 2019
28. Case 25-2011
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Aliyah R. Sohani, Carol C. Wu, and Edward J. Benz
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Diagnostic Test Result ,medicine.medical_specialty ,Pediatrics ,Paraspinal masses ,business.industry ,Anemia ,hemic and lymphatic diseases ,Microcytic anemia ,medicine ,General Medicine ,medicine.disease ,business ,Surgery - Abstract
A 62-year-old woman was seen at this hospital because of dyspnea, anemia, and paraspinal masses. Examination revealed splenomegaly. Laboratory studies revealed microcytic anemia. A diagnostic test result was received.
- Published
- 2011
29. Targeting the Cell Death-Survival Equation
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Edward J. Benz, Nika N. Danial, David G. Nathan, and Ravi K. Amaravadi
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Gerontology ,Clinical Trials as Topic ,Cancer Research ,Focus (computing) ,Cell Death ,Cell Survival ,Antineoplastic Agents ,Data science ,Structure and function ,Oncology ,Neoplasms ,Animals ,Humans ,Sociology ,Signal Transduction - Abstract
This issue of CCR Focus comprises four representative articles that closely fit the research interests of Stanley J. Korsmeyer, to whom this volume is dedicated. The first article, and perhaps the most related to Korsmeyer's work, is a review by Nika Danial of the structure and function of the ever
- Published
- 2007
30. Development of an Integrated Approach to Cancer Disparities: One Cancer Center's Experience
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Karen Burns White, Karen M. Emmons, and Edward J. Benz
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Gerontology ,Epidemiology ,Cancer Care Facilities ,Critical infrastructure ,Neoplasms ,medicine ,Humans ,Minority Health ,Minority Groups ,Clinical Trials as Topic ,Delivery of Health Care, Integrated ,Extramural ,business.industry ,Cancer ,Neoplasms therapy ,Health Status Disparities ,Integrated approach ,medicine.disease ,Community-Institutional Relations ,Competency-Based Education ,National Cancer Institute (U.S.) ,United States ,Oncology ,Minority health ,Cancer disparities ,business - Abstract
The National Cancer Institute's (NCI) Cancer Centers Program has provided a critical infrastructure for discovery related to the causes, prevention, and treatment of cancer. This program spends more than $200 million annually to fund 39 comprehensive cancer centers in 24 states. The substantial
- Published
- 2007
31. In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs
- Author
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Carolyn D. Runowicz, Andrew I. Schafer, Waun Ki Hong, F. Marc Stewart, Deepa Bhojwani, Elihu H. Estey, Kanti R. Rai, Walter J. Curran, Jerald P. Radich, Peter L. Greenberg, Jordan U. Gutterman, Gary H. Lyman, Edward J. Benz, Ayalew Tefferi, Oliver W. Press, Ross L. Levine, John M. Bennett, Clara D. Bloomfield, Isaiah J. Fidler, Hal E. Broxmeyer, Karen H. Antman, Gabriel N. Hortobagyi, Jean Pierre J. Issa, Mary M. Horowitz, Therese M. Mulvey, Massimo Cristofanilli, Hagop M. Kantarjian, Asher Chanan-Khan, Morie A. Gertz, Margaret L. Kripke, Robert C. Bast, David Khayat, Theodore S. Lawrence, Francisco J. Esteva, James P. Allison, Stephen J. Forman, Charles A. Lemaistre, John W. Adamson, Michael P. Link, Larry Baker, George P. Canellos, Nancy Berliner, Wendy Stock, Yoav H. Messinger, David P. Steensma, Ranjana H. Advani, James M. Foran, Jorge E. Cortes, Brenda M. Sandmaier, Philip W. Kantoff, Daniel J. DeAngelo, Lillian L. Siu, Charles A. Schiffer, Joseph R. Bertino, Julie M. Vose, Thomas J. Kipps, Steven Coutre, Charles D. Blanke, Josef T. Prchal, Naoto T. Ueno, Clifford A. Hudis, Andrew D. Zelenetz, Saul A. Rosenberg, Hope S. Rugo, Raphael E. Pollock, George Q. Daley, Harvey M. Golomb, Bruce D. Cheson, Robert I. Handin, Sagar Lonial, Robert A. Kyle, Anas Younes, Louise C. Strong, Sergio Giralt, Bruce E. Johnson, Richard A. Van Etten, Paulo M. Hoff, Emil J. Freireich, Neal J. Meropol, Richard T. Silver, Rainer Storb, Ronald Hoffman, Alan Saven, Susan O'Brien, Michael A. Thompson, Ravi Bhatia, Harry P. Erba, Jacob M. Rowe, Maurie Markman, Susan L. Cohn, Richard Stone, Bruce A. Chabner, Charles S. Fuchs, Richard A. Larson, Mikkael A. Sekeres, Roman Perez-Soler, Scott M. Lippman, Eric P. Winer, James N. George, Lawrence H. Einhorn, Fernando Cabanillas, S. Vincent Rajkumar, Peter H. Wiernik, John C. Byrd, Bayard D. Clarkson, Fadlo R. Khuri, Linda D. Bosserman, Kenneth Kaushansky, Samuel Hellman, John Mendelsohn, Martin S. Tallman, Smita Bhatia, H. Joachim Deeg, J L Abkowitz, and Gerardo Colon-Otero
- Subjects
Prescription Fees ,Cancer drugs ,Library science ,Antineoplastic Agents ,Patient Advocacy ,General Medicine ,Medical and Health Sciences ,Drug Costs ,United States ,Article ,GEORGE (programming language) ,Neoplasms ,Prescription Fee ,Political science ,Humans ,Patient Participation ,Humanities - Abstract
Author(s): Tefferi, Ayalew; Kantarjian, Hagop; Rajkumar, S Vincent; Baker, Lawrence H; Abkowitz, Jan L; Adamson, John W; Advani, Ranjana Hira; Allison, James; Antman, Karen H; Bast, Robert C; Bennett, John M; Benz, Edward J; Berliner, Nancy; Bertino, Joseph; Bhatia, Ravi; Bhatia, Smita; Bhojwani, Deepa; Blanke, Charles D; Bloomfield, Clara D; Bosserman, Linda; Broxmeyer, Hal E; Byrd, John C; Cabanillas, Fernando; Canellos, George Peter; Chabner, Bruce A; Chanan-Khan, Asher; Cheson, Bruce; Clarkson, Bayard; Cohn, Susan L; Colon-Otero, Gerardo; Cortes, Jorge; Coutre, Steven; Cristofanilli, Massimo; Curran, Walter J; Daley, George Q; DeAngelo, Daniel J; Deeg, H Joachim; Einhorn, Lawrence H; Erba, Harry P; Esteva, Francisco J; Estey, Elihu; Fidler, Isaiah J; Foran, James; Forman, Stephen; Freireich, Emil; Fuchs, Charles; George, James N; Gertz, Morie A; Giralt, Sergio; Golomb, Harvey; Greenberg, Peter; Gutterman, Jordan; Handin, Robert I; Hellman, Samuel; Hoff, Paulo Marcelo; Hoffman, Ronald; Hong, Waun Ki; Horowitz, Mary; Hortobagyi, Gabriel N; Hudis, Clifford; Issa, Jean Pierre; Johnson, Bruce Evan; Kantoff, Philip W; Kaushansky, Kenneth; Khayat, David; Khuri, Fadlo R; Kipps, Thomas J; Kripke, Margaret; Kyle, Robert A; Larson, Richard A; Lawrence, Theodore S; Levine, Ross; Link, Michael P; Lippman, Scott M; Lonial, Sagar; Lyman, Gary H; Markman, Maurie; Mendelsohn, John; Meropol, Neal J; Messinger, Yoav; Mulvey, Therese M; O'Brien, Susan; Perez-Soler, Roman; Pollock, Raphael; Prchal, Josef
- Published
- 2015
32. Restructuring the academic department of internal medicine
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Edward J. Benz and Arthur M. Feldman
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Faculty, Medical ,Organizational innovation ,Higher education ,business.industry ,Restructuring ,MEDLINE ,Historical Article ,General Medicine ,History, 20th Century ,Organizational Innovation ,Nursing ,Academic department ,Internal Medicine ,Humans ,Organizational Objectives ,Medicine ,Medical history ,business ,Schools, Medical - Published
- 2005
33. An erythroid differentiation–specific splicing switch in protein 4.1R mediated by the interaction of SF2/ASF with an exonic splicing enhancer
- Author
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Edward J. Benz, Guang Yang, Jane Y. Wu, and Shu-Ching Huang
- Subjects
Immunology ,Exonic splicing enhancer ,Biology ,Biochemistry ,Mice ,Splicing factor ,Exon ,SR protein ,Erythroid Cells ,Cell Line, Tumor ,Animals ,Humans ,Enhancer ,Binding Sites ,Serine-Arginine Splicing Factors ,Alternative splicing ,Membrane Proteins ,Nuclear Proteins ,RNA-Binding Proteins ,Cell Differentiation ,Exons ,Cell Biology ,Hematology ,Molecular biology ,Alternative Splicing ,Cytoskeletal Proteins ,RNA splicing ,Minigene - Abstract
Protein 4.1R is a vital component of the red blood cell membrane cytoskeleton. Promotion of cytoskeletal junctional complex stability requires an erythroid differentiation stage–specific splicing switch promoting inclusion of exon 16 within the spectrin/actin binding domain. We showed earlier that an intricate combination of positive and negative RNA elements controls exon 16 splicing. In this report, we further identified 3 putative exonic splicing enhancers within exon 16 and investigated the function of the sequence CAGACAT in the regulation of exon 16 splicing. Mutation of these sequences leads to increased exclusion of exon 16 in both in vivo and in vitro splicing assays, indicating that CAGACAT is a functional exonic splicing enhancer. UV cross-linking further detects an approximately 33-kDa protein that specifically binds to the CAGACAT-containing transcript. An anti-SF2/ASF antibody specifically immunoprecipitates the approximately 33-kDa protein. Furthermore, SF2/ASF stimulates exon 16 inclusion in both in vitro complementation assays and minigene-transfected mouse erythroleukemia cells (MELCs). Finally, SF2/ASF expression is up-regulated and correlates with exon 16 inclusion in differentiated MELCs. These results suggest that increased splicing factor 2/alternative splicing factor (SF2/ASF) expression in differentiated mouse erythroleukemia mediates a differentiation stage–specific exon 16 splicing switch through its interaction with the exonic splicing enhancer.
- Published
- 2005
34. Mitotic Regulation of Protein 4.1R Involves Phosphorylation by cdc2 Kinase
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Siu-Hong Chan, Heidi T. Cho, Edward J. Benz, Eva S. Liu, Shu-Ching Huang, Ramasamy Jagadeeswaran, and Indira D. Munagala
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DNA, Complementary ,Cell division ,Molecular Sequence Data ,Mitosis ,Spindle Apparatus ,Biology ,Spindle pole body ,Tubulin ,Microtubule ,Humans ,Protein Isoforms ,Amino Acid Sequence ,Phosphorylation ,RNA, Small Interfering ,Fluorescent Antibody Technique, Indirect ,Cytoskeleton ,Interphase ,Molecular Biology ,Gene Library ,Cell Nucleus ,Cyclin-dependent kinase 1 ,Reverse Transcriptase Polymerase Chain Reaction ,Membrane Proteins ,Articles ,Cell Biology ,Protein Structure, Tertiary ,Spindle apparatus ,Cell biology ,Cytoskeletal Proteins ,Phenotype ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,HeLa Cells ,Plasmids - Abstract
The nonerythrocyte isoform of the cytoskeletal protein 4.1R (4.1R) is associated with morphologically dynamic structures during cell division and has been implicated in mitotic spindle function. In this study, we define important 4.1R isoforms expressed in interphase and mitotic cells by RT-PCR and mini-cDNA library construction. Moreover, we show that 4.1R is phosphorylated by p34cdc2kinase on residues Thr60 and Ser679 in a mitosis-specific manner. Phosphorylated 4.1R135isoform(s) associate with tubulin and Nuclear Mitotic Apparatus protein (NuMA) in intact HeLa cells in vivo as well as with the microtubule-associated proteins in mitotic asters assembled in vitro. Recombinant 4.1R135is readily phosphorylated in mitotic extracts and reconstitutes mitotic aster assemblies in 4.1R-immunodepleted extracts in vitro. Furthermore, phosphorylation of these residues appears to be essential for the targeting of 4.1R to the spindle poles and for mitotic microtubule aster assembly in vitro. Phosphorylation of 4.1R also enhances its association with NuMA and tubulin. Finally, we used siRNA inhibition to deplete 4.1R from HeLa cells and provide the first direct genetic evidence that 4.1R is required to efficiently focus mitotic spindle poles. Thus, we suggest that 4.1R is a member of the suite of direct cdc2 substrates that are required for the establishment of a bipolar spindle.
- Published
- 2005
35. An Interview with Saul Weingart
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Edward J. Benz
- Subjects
Leadership and Management ,business.industry ,Medicine ,business - Published
- 2013
36. A splicing alteration of 4.1R pre-mRNA generates 2 protein isoforms with distinct assembly to spindle poles in mitotic cells
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Laure Croisille, Faouzi Baklouti, Jean Delaunay, Edward J. Benz, Madeleine Morinière, François Delhommeau, Gabriel Tamagnini, Pierre-Olivier Schischmanoff, Gil Tchernia, Letícia Ribeiro, Patricia Rince, Philippe Leclerc, and Corinne Vasseur-Godbillon
- Subjects
Molecular Sequence Data ,Immunology ,Mitosis ,Spindle Apparatus ,Biology ,medicine.disease_cause ,Biochemistry ,Spindle pole body ,Exon ,Sequence Homology, Nucleic Acid ,RNA Precursors ,medicine ,Humans ,Protein Isoforms ,Amino Acid Sequence ,DNA Primers ,Centrosome ,Mutation ,Base Sequence ,Sequence Homology, Amino Acid ,Reverse Transcriptase Polymerase Chain Reaction ,Neuropeptides ,Membrane Proteins ,Proteins ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,Recombinant Proteins ,Spindle apparatus ,Cell biology ,Alternative Splicing ,Cytoskeletal Proteins ,RNA splicing ,Precursor mRNA ,Sequence Alignment ,Cell Division - Abstract
The C-terminal region of erythroid cytoskeletal protein 4.1R, encoded by exons 20 and 21, contains a binding site for nuclear mitotic apparatus protein (NuMA), a protein needed for the formation and stabilization of the mitotic spindle. We have previously described a splicing mutation of 4.1R that yields 2 isoforms: One, CO.1, lacks most of exon 20-encoded peptide and carries a missense C-terminal sequence. The other, CO.2, lacks exon 20-encoded C-terminal sequence, but retains the normal exon 21-encoded C-terminal sequence. Knowing that both shortened proteins are expressed in red cells and assemble to the membrane skeleton, we asked whether they would ensure 4.1R mitotic function in dividing cells. We show here that CO.2, but not CO.1, assembles to spindle poles, and colocalizes with NuMA in erythroid and lymphoid mutated cells, but none of these isoforms interact with NuMA in vitro. In microtubule-destabilizing conditions, again only CO.2 localizes to the centrosomes. These data suggest that the stability of 4.1R association with centrosomes requires an intact C-terminal end, either for a proper conformation of the protein, for a direct binding to an unknown centrosome-cytoskeletal network, or for both. We also found that 4.1G, a ubiquitous homolog of 4.1R, is present in mutated as well as control cells and that its C-terminal region binds efficiently to NuMA, suggesting that in fact mitotic spindles host a mixture of the two 4.1 family members. These findings led to the postulate that the coexpression at the spindle poles of 2 related proteins, 4.1R and 4.1G, might reflect a functional redundancy in mitotic cells.
- Published
- 2002
37. Reassignment of theEPB4·1gene to 1p36 and assessment of its involvement in neuroblastomas
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Steve Huang, Chaoyu Wang, Holger Christiansen, Mohini Lutchman, U. D. Lichtenauer, J. Torres-Cruz, Svetlana Pack, Barbara Dockhorn-Dworniczak, Edward J. Benz, Athar H. Chishti, Christopher Poremba, Christian A. Koch, A. C. Kim, Alexander O. Vortmeyer, Zhengping Zhuang, and S. C. Huang
- Subjects
medicine.diagnostic_test ,Clinical Biochemistry ,Alternative splicing ,General Medicine ,Biology ,Biochemistry ,Molecular biology ,Exon ,Complementary DNA ,RNA splicing ,Gene expression ,medicine ,Missense mutation ,Gene ,Fluorescence in situ hybridization - Abstract
ObjectivesEPB4·1 has been previously mapped to human chromosome 1p33-p34.2. In contradiction to this chromosomal location, we have mapped EPB4·1–1p36 by using fluorescence in situ hybridization and radiation hybrid mapping. In neuroblastomas, deletions of the telomeric end of chromosome 1 (1p36) are the most common genetic aberration. Methods We investigated whether genetic aberrations of EPB4·1 can be detected in some neuroblastomas by analyzing 72 tumours for EPB4·1 mutation, expression, and alternative splicing pattern. Furthermore, EPB4·1 protein from a neuroblastoma cell line was studied for its subcellular localization. Results Sequence changes could be detected in 14 out of 72 neuroblastomas, including missense, silent, and intronic changes. Duplex RT-PCR analysis revealed a subset of 11 tumours expressing significantly low levels of EPB4·1. Significant EPB4·1 sequence changes that were detected included an exon 4 G/A missense mutation (amino acid: V/I) that was shown to be associated with absence of wild-type EPB4·1 expression (3 tumours), an exon 8 G/A missense mutation (V/M) (1 tumour), and an intronic sequence change that was shown to be associated with the presence of an aberrant transcript (1 tumour). Splicing pattern analysis revealed that all EPB4·1 transcripts from tumours exclude exon 3, a splicing pattern for generating the 135 kDa isoform. EPB4·1 cDNA cloned from a neuroblastoma cell line produced a 135-kDa protein with a cytoplasm/membrane localization. Conclusions Out of 72 neuroblastomas we have identified 11 tumours with impaired EPB4·1 expression and 5 tumours with significant sequence changes. We also found that the 135 kDa isoform is the main EPB4·1 product in neuroblastoma. EPB4·1 cDNA from a neuroblastoma cell line produced a 135-kDa protein and displayed a cytoplasm/membrane localization in transfected cells.
- Published
- 2001
38. The Prototypical 4.1R-10-kDa Domain and the 4.1G-10-kDa Paralog Mediate Fodrin-Actin Complex Formation
- Author
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Edward J. Benz, Aikaterini Kontrogianni-Konstantopoulos, Carole S. Frye, and Shu-Ching Huang
- Subjects
Gene isoform ,Molecular Sequence Data ,Complex formation ,Biology ,Biochemistry ,Homology (biology) ,Mice ,Exon ,Biopolymers ,In vivo ,Sequence Homology, Nucleic Acid ,Tumor Cells, Cultured ,Homologous chromosome ,Animals ,Humans ,Protein Isoforms ,Amino Acid Sequence ,Promoter Regions, Genetic ,Molecular Biology ,Actin ,Neurons ,Base Sequence ,Sequence Homology, Amino Acid ,Reverse Transcriptase Polymerase Chain Reaction ,Microfilament Proteins ,DNA ,Exons ,Cell Biology ,Rat brain ,Molecular biology ,Actins ,Rats ,Alternative Splicing ,Carrier Proteins - Abstract
A complex family of 4.1R isoforms has been identified in non-erythroid tissues. In this study we characterized the exonic composition of brain 4.1R-10-kDa or spectrin/actin binding (SAB) domain and identified the minimal sequences required to stimulate fodrin/F-actin association. Adult rat brain expresses predominantly 4.1R mRNAs that carry an extended SAB, consisting of the alternative exons 14/15/16 and part of the constitutive exon 17. Exon 16 along with sequences carried by exon 17 is necessary and sufficient to induce formation of fodrin-actin-4.1R ternary complexes. The ability of the respective SAB domains of 4.1 homologs to sediment fodrin/actin was also investigated. 4.1G-SAB stimulates association of fodrin/actin, although with an approximately 2-fold reduced efficiency compared with 4.1R-10-kDa, whereas 4.1N and 4.1B do not. Sequencing of the corresponding domains revealed that 4.1G-SAB carries a cassette that shares significant homology with 4.1R exon 16, whereas the respective sequence is divergent in 4.1N and absent from brain 4.1B. An approximately 150-kDa 4.1R and an approximately 160-kDa 4.1G isoforms are present in PC12 lysates that occur in vivo in a supramolecular complex with fodrin and F-actin. Moreover, proteins 4.1R and 4.1G are distributed underneath the plasma membrane in PC12 cells. Collectively, these observations suggest that brain 4.1R and 4.1G may modulate the membrane mechanical properties of neuronal cells by promoting fodrin/actin association.
- Published
- 2001
39. Characterization of the Interaction between Protein 4.1R and ZO-2
- Author
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Edward J. Benz, Shu-Ching Huang, Subhendra N. Mattagajasingh, and Julia S. Hartenstein
- Subjects
Tight junction ,biology ,Arp2/3 complex ,Cell Biology ,Occludin ,Actin cytoskeleton ,Biochemistry ,Cell biology ,Adherens junction ,Zonula Occludens-2 Protein ,biology.protein ,Spectrin ,Cytoskeleton ,Molecular Biology - Abstract
Multiple isoforms of the red cell protein 4.1R are expressed in nonerythroid cells, including novel 135-kDa isoforms. Using a yeast two-hybrid system, immunocolocalization, immunoprecipitation, and in vitro binding studies, we found that two 4.1R isoforms of 135 and 150 kDa specifically interact with the protein ZO-2 (zonula occludens-2). 4.1R is colocalized with ZO-2 and occludin at Madin-Darby canine kidney (MDCK) cell tight junctions. Both isoforms of 4.1R coprecipitated with proteins that organize tight junctions such as ZO-2, ZO-1, and occludin. Western blot analysis also revealed the presence of actin and alpha-spectrin in these immunoprecipitates. Association of 4.1R isoforms with these tight junction and cytoskeletal proteins was found to be specific for the tight junction and was not seen in nonconfluent MDCK cells. The amino acid residues that sustain the interaction between 4.1R and ZO-2 reside within the amino acids encoded by exons 19-21 of 4.1R and residues 1054-1118 of ZO-2. Exogenously expressed 4.1R containing the spectrin/actin- and ZO-2-binding domains was recruited to tight junctions in confluent MDCK cells. Taken together, our results suggest that 4.1R might play an important role in organization and function of the tight junction by establishing a link between the tight junction and the actin cytoskeleton.
- Published
- 2000
40. A Nonerythroid Isoform of Protein 4.1R Interacts with the Nuclear Mitotic Apparatus (NuMA) Protein
- Author
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Edward J. Benz, Vincent T. Marchesi, Subhendra N. Mattagajasingh, Julia S. Hartenstein, Shu-Ching Huang, and Michael Snyder
- Subjects
Macromolecular Substances ,RNA Splicing ,Recombinant Fusion Proteins ,Molecular Sequence Data ,Mitosis ,Cell Cycle Proteins ,Nerve Tissue Proteins ,Saccharomyces cerevisiae ,Spindle Apparatus ,Biology ,Kidney ,Spindle pole body ,Cell Line ,Dogs ,protein 4.1R ,Nuclear Matrix-Associated Proteins ,dynactin ,medicine ,Animals ,Humans ,Protein Isoforms ,Amino Acid Sequence ,Nuclear protein ,Interphase ,dynein ,Binding Sites ,Cell Cycle ,Neuropeptides ,Dyneins ,Membrane Proteins ,Nuclear Proteins ,Antigens, Nuclear ,Cell Biology ,Dynactin Complex ,Cell cycle ,Nuclear matrix ,Cell biology ,Spindle apparatus ,Cell nucleus ,Cytoskeletal Proteins ,medicine.anatomical_structure ,NuMA ,mitotic spindle ,Dynactin ,Microtubule-Associated Proteins ,Regular Articles ,HeLa Cells ,Protein Binding - Abstract
Red blood cell protein 4.1 (4.1R) is an 80- kD erythrocyte phosphoprotein that stabilizes the spectrin/actin cytoskeleton. In nonerythroid cells, multiple 4.1R isoforms arise from a single gene by alternative splicing and predominantly code for a 135-kD isoform. This isoform contains a 209 amino acid extension at its NH2 terminus (head piece; HP). Immunoreactive epitopes specific for HP have been detected within the cell nucleus, nuclear matrix, centrosomes, and parts of the mitotic apparatus in dividing cells. Using a yeast two-hybrid system, in vitro binding assays, coimmunolocalization, and coimmunoprecipitation studies, we show that a 135-kD 4.1R isoform specifically interacts with the nuclear mitotic apparatus (NuMA) protein. NuMA and 4.1R partially colocalize in the interphase nucleus of MDCK cells and redistribute to the spindle poles early in mitosis. Protein 4.1R associates with NuMA in the interphase nucleus and forms a complex with spindle pole organizing proteins, NuMA, dynein, and dynactin during cell division. Overexpression of a 135-kD isoform of 4.1R alters the normal distribution of NuMA in the interphase nucleus. The minimal sequence sufficient for this interaction has been mapped to the amino acids encoded by exons 20 and 21 of 4.1R and residues 1788–1810 of NuMA. Our results not only suggest that 4.1R could, possibly, play an important role in organizing the nuclear architecture, mitotic spindle, and spindle poles, but also could define a novel role for its 22–24-kD domain.
- Published
- 1999
41. Discussion
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Costa St, Edward J. Benz, and Clayton Cp
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Medical education ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,General Medicine ,Investment (macroeconomics) ,business - Published
- 1998
42. A tribute to Emil Frei III
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David G. Nathan and Edward J. Benz
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Gerontology ,medicine.medical_specialty ,Childhood leukemia ,business.industry ,education ,Tribute ,Cancer ,Combination chemotherapy ,General Medicine ,medicine.disease ,Obituary ,humanities ,Amethopterin ,Breast cancer ,Family medicine ,Combination cancer therapy ,medicine ,business ,Resistance (creativity) - Abstract
Dr. Emil Frei III, one of the fathers of combination chemotherapy for cancer, died after a prolonged illness in May of 2013. He was 89 years old (Figure (Figure11). Figure 1 Emil Frei III. Known to his colleagues, family, and friends as Tom, Frei was the emeritus director and emeritus physician-in-chief of the Dana-Farber Cancer Institute and the Richard and Susan Smith Distinguished Professor of Medicine emeritus at Harvard Medical School. A highly distinguished clinical investigator, Frei held leadership positions of major responsibility at the National Cancer Institute (NCI) in Bethesda, Maryland, and at the M.D. Anderson Cancer Center in Houston, Texas, before his appointment at Harvard. Frei was born in St. Louis on February 21, 1924, where his paternal grandfather had founded Emil Frei and Associates, a well-known stained glass company. He attended St. Louis University and then joined the United States Navy in World War II. The Navy sent him to Colgate University and then to Yale University for medical training. He graduated from Yale Medical School in 1948 and later served in the Navy Medical Corps during the Korean War. In 1955, Frei and his close colleague Emil J. Freireich were recruited to the expanding clinical program at the NCI by Gordon Zubrod, then the newly appointed NCI clinical director. Supported by Zubrod’s superb guidance and defense, Frei and Freireich began their controversial studies of the treatment of acute leukemia in childhood. This work revolutionized the management of that cruel disease and forever altered the medical treatment of cancer. Modern cancer chemotherapy began with the studies of what turned out to be folate reductase inhibitors by Sidney Farber and his associates in the mid-1940s. At that time, children with acute leukemia died rapidly — half of any cohort expired in three months. Farber’s use of a single agent, then aminopterin and later amethopterin, produced some complete remissions, but these were generally short-lived due to the development of resistance. (Later Fred Alt and his colleagues showed that resistance to folic acid reductase inhibitors was due to the emergence of leukemic cells with ever-increasing levels of the enzyme.) Acknowledging the problem of resistance, Farber held that more effective drugs were needed that would attack different pathways. He believed that such drugs should be given sequentially to maintain remission after relapse occurred. Farber’s proposed use of sequential chemotherapy (assuming that new drugs could be found) was opposed by Abraham Goldin and Lloyd Law at the NCI as well as Howard Skipper and Frank Schabel at the Southern Research Institute in Alabama, who were experts in the drug treatment of leukemic cell lines and murine leukemia. They held that combinations of drugs with different targets given simultaneously provided the only hope for sustained remissions, since most cancers have infinite ways of finding their way around single agents. Zubrod, whose military medicine experience was in the malaria program of World War II, saw childhood leukemia as the cancer equivalent of malaria and agreed with the basic scientists. He urged Frei and Freireich to combine drugs as they were produced to treat leukemia in childhood, to collaborate with other like-minded physicians, and to train younger physicians to learn the new paradigm of cancer chemotherapy on the wards of the NCI. Frei committed himself to decades of effort and ultimately was highly successful in all of these endeavors. The development of the VAMP program (a combination of vincristine, amethopterin, 6-mercaptopurine, and prednisone) led to long-term remissions and many cures. The later addition of more agents, such as adriamycin and asparaginase, has brought the cure rate of childhood leukemia close to 90%. Frei’s collaborative and training efforts are best demonstrated by the highly unusual results of the Lasker Prize deliberations in 1972. In 1966, only Sidney Farber received a Lasker Prize in clinical medicine. In 1972, no less than 16 pioneers of effective combination cancer therapy were so honored. Among them were Zubrod, Frei, and Freireich and several of their trainees and collaborators. Frei remained at the NCI for over a decade. Among his many accomplishments there was the training of Vincent DeVita, who initiated successful studies of combination chemotherapy in Hodgkin disease and, with George Canellos, developed an important adjuvant combination chemotherapy program for breast cancer. Frei then moved with Freireich to the M.D. Anderson Cancer Center before he assumed his leadership of cancer medicine at Harvard and the Dana-Farber Cancer Institute in 1972. He remained in those posts until he retired. At Dana-Farber, Frei built a strong basic cancer biology program, massively expanded biostatistics and clinical trial expertise, recruited and trained excellent young clinical scientists, created a renowned cancer immunology program, and greatly strengthened the Dana-Farber leukemia and breast cancer programs. He resumed his interest in pediatric oncology and contributed to the development of Stephen Sallan as an international leader of clinical trials in acute childhood leukemia. He launched Dana-Farber and Boston Children’s Hospital into a concerted effort to manage osteosarcoma. His most famous osteosarcoma patient, Edward M. Kennedy Jr., was recently quoted as saying, “I honestly believe that Dr. Frei saved my life” (ref. 1; Figure Figure22). Figure 2 Emil Frei III with Edward M. Kennedy Jr. Frei’s encyclopedic knowledge of cancer chemotherapy made him an invaluable teacher. His textbook, Cancer Medicine, became the leading book of its kind in the United States. With all of that prestige, Tom Frei was forever down-to-earth, optimistic, supportive, kind, and generous. He is sorely missed, but his impact on cancer treatment will remain with us for many years.
- Published
- 2013
43. Asynchronous regulation of splicing events within protein 4.1 pre-mRNA during erythroid differentiation
- Author
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Vincent T. Marchesi, Shu-Ching Huang, Jean Delaunay, Edward J. Benz, Faouzi Baklouti, and Tang K. Tang
- Subjects
Protein isoform ,Splice site mutation ,Immunology ,Alternative splicing ,Exonic splicing enhancer ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Molecular biology ,Exon ,RNA splicing ,Spectrin ,Precursor mRNA - Abstract
Protein 4.1 is an 80-kD structural component of the red blood cell (RBC) cytoskeleton. It is critical for the formation of the spectrin/actin/protein 4.1 junctional complex, the integrity of which is important for the horizontal strength and elasticity of RBCs. We and others have previously shown that multiple protein 4.1 mRNA isoforms are generated from a single genomic locus by several alternative mRNA splicing events, leading to the insertion or skipping of discrete internal sequence motifs. The physiologic significance of these motifs: (1) an upstream 17-nucleotide sequence located at the 5′ end of exon 2 that contains an in-frame ATG initiation codon, the inclusion of which by use of an alternative splice acceptor site in exon 2 allows the production of a 135-kD high-molecular-weight isoform present in nonerythroid cells; (2) exon 16, which encodes a 21-amino acid (21aa) segment located in the 10-kD “spectrin/actin binding domain” (SAB), the presence of which is required for junctional complex stability in RBCs. Previous studies by our group and others suggested that, among blood cells, this exon was retained only in mature mRNA in the erythroid lineage. Exon 16 is one of a series of three closely linked alternatively spliced exons, generating eight possible mRNA products with unique configurations of the SAB. In this communication, we report studies of the expression of both the translation initiation region and the SAB region during induced erythroid maturation in mouse erythroleukemia (MEL) cells. We have found that only two of eight possible combinatorial patterns of exon splicing at the SAB region are encountered: the isoform lacking all three exons, present in predifferentiated cells, and the isoform containing only exon 16, which increases in amount during erythroid differentiation. The protein isoform containing the 21aa segment encoded by exon 16 efficiently and exclusively incorporates into the membrane, whereas the isoform lacking this 21aa segment remains in the cytoplasm, as well as the membrane. In contrast with exon 16, the erythroid pattern of exon 2 splicing, i.e., skipping of the 17-base sequence at the 5′ end, was found to be already established in the uninduced MEL cells, suggesting strongly that this regulated splicing event occurs at an earlier stage of differentiation. Our results demonstrate asynchronous regulation of two key mRNA splicing events during erythroid cell maturation. These findings also show that the splicing of exon 16 alters the intracellular localization of protein 4.1 in MEL cells, and appears to be essential for its targeting to the plasmalemma.
- Published
- 1996
44. Na, K-ATPase isoform gene expression in normal and hypertrophied dog heart
- Author
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Edward J. Benz, Maureen Gilmore-Hebert, Raphael Zahler, and W. Sun
- Subjects
Gene isoform ,medicine.medical_specialty ,Physiology ,ATPase ,Blotting, Western ,Gene Expression ,Left ventricular hypertrophy ,Muscle hypertrophy ,Dogs ,Physiology (medical) ,Internal medicine ,Gene expression ,medicine ,Animals ,RNA, Messenger ,Na+/K+-ATPase ,Fluorescent Antibody Technique, Indirect ,Pressure overload ,Analysis of Variance ,Messenger RNA ,biology ,Chemistry ,Myocardium ,Blotting, Northern ,medicine.disease ,Isoenzymes ,Endocrinology ,biology.protein ,Hypertrophy, Left Ventricular ,Sodium-Potassium-Exchanging ATPase ,Cardiology and Cardiovascular Medicine - Abstract
The catalytic alpha subunit of the sodium-potassium ATPase, the target of digitalis glycosides, has three isoforms; the expression of these isoforms is tissue-specific and developmentally regulated. While the effect of pressure overload on Na, K-ATPase isoform expression has been studied in rodent heart, there are no systematic data on this question in hearts of larger animals, which differ from those of rodents both in isoform composition and in glycoside sensitivity. Thus, we investigated the expression of Na, K-ATPase isoforms in normal dog heart; we also examined the effect of experimental left ventricular hypertrophy on isoform expression.hypertrophy was produced by aortic banding. Expression was assessed by quantitative Northern and Western blotting, immunofluorescence, and 3H-ouabain binding.RNA blotting indicated that the alpha 3 isoform represented 11% of Na, K-ATPase mRNA in normal dog LV. Normal dog LV expressed alpha 1 and alpha 3 protein, but no detectable alpha 2; immunoreactive alpha 1 and alpha 3 protein were also present in Purkinje fibers. There was a statistically significant decrease in total expression of all alpha isoform mRNA's in hypertrophied dog LV, resulting in a greater proportion of alpha 1. The expression level of the alpha 3 isoform mRNA and protein was lower in hypertrophied hearts.These results indicate a greater proportion of alpha 1 isoform pumps in experimental canine hypertrophy. Thus, shifts in NA, K-ATPase isoforms occur in pressure-overloaded heart in large animals as well as rodents.
- Published
- 1996
45. RBFOX2 promotes protein 4.1R exon 16 selection via U1 snRNP recruitment
- Author
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Guang Yang, Shu-Ching Huang, Anyu Zhou, Faye Yu, Alexander C. Ou, Edward J. Benz, Brian Yu, Jennie Park, and Angela Lee
- Subjects
RNA Splicing ,Exonic splicing enhancer ,RNA-binding protein ,Biology ,Ribonucleoprotein, U1 Small Nuclear ,Exon ,Splicing factor ,Consensus sequence ,Humans ,snRNP ,Molecular Biology ,Splice site mutation ,Base Sequence ,Membrane Proteins ,RNA-Binding Proteins ,Zinc Fingers ,Cell Biology ,Exons ,Articles ,Ribonucleoproteins, Small Nuclear ,Molecular biology ,Protein Structure, Tertiary ,Repressor Proteins ,Cytoskeletal Proteins ,HEK293 Cells ,RNA splicing ,RNA Splicing Factors ,HeLa Cells - Abstract
The erythroid differentiation-specific splicing switch of protein 4.1R exon 16, which encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability, is modulated by the differentiation-induced splicing factor RBFOX2. We have now characterized the mechanism by which RBFOX2 regulates exon 16 splicing through the downstream intronic element UGCAUG. Exon 16 possesses a weak 5′ splice site (GAG/GTTTGT), which when strengthened to a consensus sequence (GAG/GTAAGT) leads to near-total exon 16 inclusion. Impaired RBFOX2 binding reduces exon 16 inclusion in the context of the native weak 5′ splice site, but not the engineered strong 5′ splice site, implying that RBFOX2 achieves its effect by promoting utilization of the weak 5′ splice site. We further demonstrate that RBFOX2 increases U1 snRNP recruitment to the weak 5′ splice site through direct interaction between its C-terminal domain (CTD) and the zinc finger region of U1C and that the CTD is required for the effect of RBFOX2 on exon 16 splicing. Our data suggest a novel mechanism for exon 16 5′ splice site activation in which the binding of RBFOX2 to downstream intronic splicing enhancers stabilizes the pre-mRNA–U1 snRNP complex through interactions with U1C.
- Published
- 2011
46. Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure
- Author
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Euy Myoung Jeong, Sassan Ghassemzadeh, Michael A. Sobieski, Amanda M. Herman, G. Bhat, Shu-Ching Huang, Antone Tatooles, Samuel C. Dudley, Edward J. Benz, An Xie, Ge Gao, Timothy J. Kamp, Anyu Zhou, Srinivasan Kasturirangan, Mihai Raicu, and Jianhua Zhang
- Subjects
Adult ,Male ,medicine.medical_specialty ,Spliceosome ,RNA Splicing ,Cardiomyopathy ,Down-Regulation ,Sudden death ,Jurkat cells ,Sodium Channels ,Article ,NAV1.5 Voltage-Gated Sodium Channel ,Splicing factor ,Jurkat Cells ,Young Adult ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Myocytes, Cardiac ,Cells, Cultured ,Embryonic Stem Cells ,Aged ,Heart Failure ,business.industry ,Gene Expression Profiling ,Nuclear Proteins ,RNA-Binding Proteins ,Middle Aged ,medicine.disease ,Angiotensin II ,Cell biology ,Up-Regulation ,Endocrinology ,Heart failure ,RNA splicing ,Spliceosomes ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background— Human heart failure is associated with decreased cardiac voltage-gated Na + channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study. Methods and Results— Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell–derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na + channel current 91.1±9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript. Conclusions— Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na + channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure.
- Published
- 2011
47. Case records of the Massachusetts General Hospital. Case 25-2011. A 62-year-old woman with anemia and paraspinal masses
- Author
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Edward J, Benz, Carol C, Wu, and Aliyah R, Sohani
- Subjects
Anemia ,Bone Marrow Cells ,Cardiomegaly ,Middle Aged ,Thoracic Vertebrae ,Diagnosis, Differential ,Radiography ,alpha-Thalassemia ,Hematopoiesis, Extramedullary ,Splenomegaly ,Humans ,Thalassemia ,Female ,Muscle, Skeletal - Published
- 2011
48. American Journal of Blood Research: Editorial Board (2011) e-Century Publishing Corporation
- Author
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Larry W, Kwak, David M, Goldenberg, Edward J, Benz, Qing, Yi, Markus, Müschen, and Dengshun, Wang
- Subjects
Editorial - Published
- 2011
49. Tissue-specific alternative splicing of protein 4.1 inserts an exon necessary for formation of the ternary complex with erythrocyte spectrin and F-actin
- Author
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Pamela S. Becker, William C. Horne, Edward J. Benz, Tang K. Tang, and Shu-Ching Huang
- Subjects
Immunology ,Alternative splicing ,Peripheral membrane protein ,EPB41 ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Spectrin ,Integral membrane protein ,Peptide sequence ,Ternary complex ,Actin - Abstract
Erythrocyte protein 4.1 is an 78- to 80-Kd peripheral membrane protein that promotes the interaction of spectrin with actin protofilaments and links the resulting interlocking network to the integral membrane proteins. There are several isoforms of protein 4.1 that appear to be expressed in a restricted group of tissues. These arise from alternative mRNA splicing events that lead to the combinational insertion or deletion of at least 10 blocks of nucleotides (motifs) within the mature mRNA. One of these, motif I, consists of 63 nucleotides encoding 21 amino acids in the N-terminal region of the putative spectrin/actin-binding domain. The expression of the motif U- containing isoform occurs late in erythroid maturation. We generated recombinant isoforms of protein 4.1 and of the putative 10-Kd spectrin/actin-binding fragment that contain or lack this 21 amino acid sequence and examined their ability to form a ternary complex with erythrocyte spectrin and F-actin. The isoforms of the complete protein and of the 10-Kd fragment that contain the sequence encoded by motif I efficiently form the ternary complex. Isoforms that lack this sequence, but are otherwise identical, do not participate in the formation of the ternary complex. These results, in conjunction with the expression of motif I during late erythroid maturation, suggest that interaction with actin and the erythroid form of spectrin is a specialized property of the erythrocyte form of protein 4.1. Alternative mRNA splicing in developing red blood cells thus plays a key adaptive role in the formation of the highly specialized erythrocyte membrane.
- Published
- 1993
50. Genomic structure of the locus encoding protein 4.1. Structural basis for complex combinational patterns of tissue-specific alternative RNA splicing
- Author
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Edward J. Benz, Guang-Hsiung Kou, Tang K. Tang, Jen-Pin Huang, Chieh-Ju C. Tang, and V. T. Marchesi
- Subjects
Genetics ,Exon ,Splice site mutation ,Exon trapping ,RNA splicing ,Alternative splicing ,Intron ,Cell Biology ,Tandem exon duplication ,Biology ,Exon shuffling ,Molecular Biology ,Biochemistry - Abstract
Protein 4.1 (P4.1) is a multifunctional protein with heterogeneity in molecular weight, intracellular localization, tissue- and development-specific expression patterns. We have analyzed the genomic structure of the locus encoding mouse P4.1 and have systematically analyzed diverse P4.1 mRNA isoforms expressed in erythroid and nonerythroid tissues. Our results indicate that the mouse protein 4.1 gene, over 90 kilobases long, comprises at least 23 exons (13 constitutive exons, 10 alternative exons) interrupted by 22 introns. The donor and acceptor splice site sequences match the consensus sequences for the exon-intron boundaries of most eukaryotic genes. No significant sequence difference was observed between splice junctions of alternative and constitutive exons. Apparently, most alternative exon-encoded peptides are located within particular functional domains of the P4.1 protein: two peptides encoded by alternative exons 4 and 5 are located near or within the glycophorin/calmodulin binding domain, whereas three other alternative exon-encoded peptides (19-amino acid encoded by exon 14, 14-amino acid encoded by exon 15, and 21-amino acid encoded by exon 16) are located near or within the spectrin-actin binding domain. Selective use of exon 2', which carries an upstream translation initiation codon (AUG), may produce an elongated P4.1 isoform (135 kDa) that is predominantly expressed in nonerythroid tissues. Combinatorial splicing of these exons may generate different isoforms that exhibit complicated tissue-specific expression patterns.
- Published
- 1993
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