University of Wisconsin School of Medicine and Public Health McArdle Lab home

Bill Sugden, Ph.D.

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B. Sugden photo James A. Miller Professor of Oncology
American Cancer Society Research Professor

A.B., 1967, Organic Chemistry, Harvard University
M.S., 1968, Physical Chemistry, Columbia University
Ph.D., 1973, Molecular Biology, Columbia University
Postdoctoral research: Karolinska Institute, Stockholm, Sweden

Office: 814 McArdle Laboratory
Telephone: Office - (608) 262-1116; Lab - (608) 262-6697
Email: sugden@oncology.wisc.edu

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Research Interests: Molecular biology of the human tumor virus, Epstein-Barr virus

Research Description: We work with Epstein-Barr Virus (EBV) because it causes several different cancers in people. EBV is a herpesvirus that causes the common, benign infectious mononucleosis, as well as lymphomas such as Burkitt's Lymphoma, most B-cell lymphomas in immunocompromised hosts, and carcinomas such as nasopharyngeal carcinoma. We study EBV both to understand its contributions to these diseases molecularly and to develop rational means to treat them.

Our research focuses on two facets of EBV pivotal to its inducing and maintaining human tumors. One gene product of EBV, LMP1, mimics cellular signaling pathways but in a ligand-independent manner. Its signaling drives proliferation of EBV-infected B-cells, but at high levels inhibits that proliferation. We are dissecting the mechanisms by which LMP1 regulates its host cell both positively and negatively. A second gene product of EBV, EBNA1, binds several elements of EBV's origin of plasmid synthesis, oriP, to mediate the synthesis and maintenance of the viral replicon in proliferating cells. EBV's replicon replicates once per S-phase and uses the cell's DNA synthetic machinery to do so. We study EBNA1 and oriP to elucidate the mechanisms by which EBV DNA is synthesized and segregated to daughter cells. We also study this viral replicon to gain insights into how EBV subverts its host's synthetic machinery to support extrachromosomal DNA synthesis. Finally we are studying EBNA1 which not only mediates replication of EBV's replicon, but also inhibits apoptosis in infectious B-cells to understand its roles in supporting survival of EBV-associated tumors. We want to target EBNA1's survival functions to develop treatments for tumors caused by EBV.

Selected recent publications

Dresang, L. R., Vereide, D. T., and Sugden, B.  Identifying Sites Bound by Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) in the Human Genome:  Defining a Position-Weighted Matrix to Predict Sites Bound by EBNA1 in Viral Genomes.  J. Virol., 83:  2930-2940, 2009.

Lee, D. Y., Lee, J., and Sugden, B.  The Unfolded Protein Response and Autophagy:  Herpesviruses Rule!  J. Virol., 83:  1168-1172, 2009.

Pratt, Z. L., Kuzembayeva, M., Sengupta, S., and Sugden, B.  The microRNAs of Epstein-Barr Virus Are Expressed at Dramatically Differing Levels Among Cell Lines.  Virology, 386:  387-397, 2009.

Vereide, D., and Sugden, B.  Proof for EBV’s Sustaining Role in Burkitt’s Lymphomas.  Semin. Cancer Biol., in press, 2009 [Epub ahead of print July 20, 2009].

Lee, D. Y., and Sugden, B.  The Latent Membrane Protein 1 Oncogene Modifies B-cell Physiology by Regulating Autophagy.  Oncogene, 27: 2833-2842, 2008.

Lee, D. Y., and Sugden, B.  The LMP1 Oncogene of EBV Activates PERK and the Unfolded Protein Response To Drive Its Own Synthesis.  Blood, 111: 2280-2289, 2008.

Lindner, S. E., Zeller, K., Schepers, A., and Sugden, B.  The Affinity of EBNA1 for Its Origin of DNA Synthesis Is a Determinant of the Origin’s Replicative Efficiency.  J. Virol., 82:  5693-5702, 2008.

Mack, A. A., and Sugden, B.  EBV Is Necessary for Proliferation of Dually Infected Primary Effusion Lymphoma Cells.  Cancer Res., 68:  6963-6968, 2008.

Sengupta, S., den Boon, J. A., Chen, I.-H., Newton, M. A., Stanhope, S. A., Cheng, Y.-J., Chen, C.-J., Hildesheim, A., Sugden, B., and Ahlquist, P.  MicroRNA 29c Is Down-regulated in Nasopharyngeal Carcinomas, Up-regulating mRNAs Encoding Extracellular Matrix Proteins.  Proc. Natl. Acad. Sci. USA, 105:  5874-5878, 2008.

Wang, C.-Y., and Sugden, B.  Identifying a Property of Origins of DNA Synthesis Required to Support Plasmids Stably in Human Cells.  Proc. Natl. Acad. Sci. USA, 105:  9639-9644, 2008.

Lee, J., and Sugden, B.  A Membrane Leucine Heptad Contributes to Trafficking, Signaling, and Transformation by Latent Membrane Protein 1.  J. Virol., 81:  9121-9130, 2007.

Lindner, S. E., and Sugden, B.  The Plasmid Replicon of Epstein-Barr Virus:  Mechanistic Insights Into Efficient, Licensed, Extrachromosomal Replication in Human Cells.  Plasmid, 58:  1-12, 2007.

Nanbo, A., Sugden, A., and Sugden, B.  The Coupling of Synthesis and Partitioning of EBV’s Plasmid Replicon Is Revealed in Live Cells.  EMBO J., 26:  4252-4262, 2007.

Altmann, M., Pich, D., Ruiss, R., Wang, J., Sugden, B., and Hammerschmidt, W.  Transcriptional Activation by EBV Nuclear Antigen 1 Is Essential for the Expression of EBV’s Transforming Genes.  Proc. Natl. Acad. Sci. USA, 103:  14188-14193, 2006.

Hammerschmidt, W., and Sugden, B.  Epstein-Barr Virus.  In:  M.L. DePamphilis (Ed.), DNA Replication and Human Disease, Chap. 34, pp. 687-705.  Cold Spring Harbor Laboratory:  Cold Spring Harbor Press, 2006.

Sengupta, S., den Boon, J. A., Chen, I.-H., Newton, M. A., Dahl, D. B., Chen, M., Cheng, Y.-J., Westra, W. H., Chen, C.-J., Hildesheim, A., Sugden, B., and Ahlquist, P.  Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma.  Cancer Res., 66:  7999-8006, 2006.

Sugden, B.  Micro Mystery Solution.  Nature, 442:  33-34, 2006.

Wang, J., Lindner, S. E., Leight, E. R., and Sugden, B. Essential Elements of a Licensed, Mammalian Plasmid Origin of DNA Synthesis. Mol. Cell. Biol., 26: 1124-1134, 2006.

Dirmeier, U., Hoffmann, R., Kilger, E., Schultheiss, U., Briseño, C., Gires, O., Kieser, A., Eick, D., Sugden, B., and Hammerschmidt, W. Latent Membrane Protein 1 of Epstein-Barr Virus Coordinately Regulates Proliferation with Control of Apoptosis. Oncogene, 24: 1711-1717, 2005.

Mack, A. A., and Sugden, B.  The Plasmid Replicon of EBV:  An Element That Underlies EBV’s Transforming Functions.  In:  E. S. Robertson (Ed.), Infection, Pathogenesis, Molecular Biology, and Control of Epstein-Barr Virus, pp. 379-402.  Horizon Press, 2005.

Perrigoue, J. G., den Boon, J. A., Friedl, A., Newton, M. A., Ahlquist, P., and Sugden, B. Lack of Association between EBV and Breast Carcinoma. Cancer Epidemiol. Biomarkers Prev., 14: 809-814, 2005.

Wang, J., and Sugden, B. Origins of Bidirectional Replication of Epstein-Barr Virus: Models for Understanding Mammalian Origins of DNA Synthesis. J. Cell. Biochem., 94: 247-256, 2005.

Hammerschmidt, W., and Sugden, B. Epstein-Barr Virus Sustains Burkitt’s Lymphomas and Hodgkin’s Disease. Trends Mol. Med., 10: 331-336, 2004.

Lam, N., Sandberg, M. L., and Sugden, B. High Physiological Levels of LMP1 Result in Phosphorylation of eIF2α in Epstein-Barr Virus-Infected Cells. J. Virol., 78: 1657-1664, 2004.

Wang, C.-Y., and Sugden, B. New Viruses Shake Old Paradigms. J. Clin. Invest., 113: 21-23, 2004.

Dirmeier, U., Neuhierl, B., Kilger, E., Reisbach, G., Sandberg, M. L., and Hammerschmidt, W. Latent Membrane Protein 1 Is Critical for Efficient Growth Transformation of Human B Cells by Epstein-Barr Virus. Cancer Res., 63: 2982-2989, 2003.

Kennedy, G., and Sugden, B. EBNA-1, a Bifunctional Transcriptional Activator. Mol. Cell. Biol., 23: 6901-6908, 2003.

Kennedy, G., and Sugden, B. Virus-based Vectors for Gene Expression in Mammalian Cells: Epstein-Barr Virus. In: S. C. Makrides (Ed.), New Comprehensive Biochemistry, Vol. 38: Gene Transfer and Expression in Mammalian Cells, Chap. 3.2, pp. 55-70. Elsevier Science B.V., 2003.

Kennedy, G., Komano, J., and Sugden, B. Epstein-Barr Virus Provides a Survival Factor to Burkitt's Lymphomas. Proc. Natl. Acad. Sci. USA, 100: 14269-14274, 2003.

Lam, N., and Sugden, B. CD40 and Its Viral Mimic, LMP1: Similar Means to Different Ends. Cell. Signal., 15: 9-16, [2002] 2003.

Lam, N., and Sugden, B. LMP1, a Viral Relative of the TNF Receptor Family, Signals Principally from Intracellular Compartments. EMBO J., 22: 3027-3038, 2003.

Kaykas, A., Worringer, K., and Sugden, B. LMP-1's Transmembrane Domains Encode Multiple Functions Required for LMP-1's Efficient Signaling. J. Virol., 76: 11551-11560, 2002.

Sugden, B. In the Beginning: a Viral Origin Exploits the Cell. Trends Biochem. Sci., 27: 1-3, 2002.

Bruening, E., and Sugden, B.Herpesviruses. In: G. Stamatoyannopoulos, P. W. Majerus, R. M. Perlmutter, and H. Varmus (Eds.), The Molecular Basis of Blood Diseases, 3rd edition, pp. 951-967. Philadelphia: W. B. Saunders Co., 2001.

Kaykas, A., Worringer, K., and Sugden, B. CD40 and LMP-1 Both Signal from Lipid Rafts but LMP-1 Assembles a Distinct, More Efficient Signaling Complex. EMBO J., 20: 2641-2654, 2001.

Kirchmaier, A. L. Analysis of Replication of oriP-Based Plasmids by Quantitative, Competitive PCR. Methods Mol. Biol., 174: 13-22, 2001.

Kirchmaier, A. L. Introduction of Plasmid Vectors into Cells Via Electroporation. Methods Mol. Biol., 174: 137-145, 2001.

Leight, E. R., and Sugden, B. Establishment of an oriP Replicon Is Dependent upon an Infrequent, Epigenetic Event. Mol. Cell. Biol., 21: 4149-4161, 2001.

Leight, E. R., and Sugden, B. The cis-Acting Family of Repeats Can Inhibit as well as Stimulate Establishment of an oriP Replicon. J. Virol., 75: 10709-10720, 2001.

Sugden, B. Howard Temin 1934-1994. A Biographical Memoir. In: National Academy of Sciences, Biographical Memoirs, Vol. 79, pp. 1-40. Washington, D.C.: The National Academy Press, 2001.

Sugden, B., and Leight, E. R. EBV's Plasmid Replicon: An Enigma in cis and trans. Curr. Top. Microbiol. Immunol., 258: 3-11, 2001.

Sugden, B., and Takada, K. Epstein-Barr Virus and Human Cancer: Hokkaido University, July 4-6, 2001. Jpn. J. Cancer Res., 92: 1352-1354, 2001.

Kaykas, A., and Sugden, B. The Amino-Terminus and Membrane-spanning Domains of LMP-1 Inhibit Cell Proliferation. Oncogene, 19: 1400-1410, 2000.

Leight, E. R., and Sugden, B. EBNA-1: a Protein Pivotal to Latent Infection by Epstein-Barr Virus. Rev. Med. Virol., 10: 83-100, 2000.

Sandberg, M. L., Kaykas, A., and Sugden, B. Latent Membrane Protein 1 of Epstein-Barr Virus Inhibits as Well as Stimulates Gene Expression. J. Virol., 74: 9755-9761, 2000.

Tu, G., Kirchmaier, A. L., Liggitt, D., Liu, Y., Liu, S., Yu, W. H., Heath, T. D., Thor, A., and Debs, R. J. Non-replicating Epstein Barr Virus-based Plasmids Extend Gene Expression and Can Improve Gene Therapy in Vivo. J. Biol. Chem., 275: 30408-30416, 2000.

Bloss, T., Kaykas, A., and Sugden, B. Dissociation of Patching by Latent Membrane Protein-1 of Epstein-Barr Virus from Its Stimulation of NF-kB Activity. J. Gen. Virol., 80: 3227-3232, 1999.

Mackey, D., and Sugden, B. Application of oriP-Plasmids and Their Mode of Replication. Methods Enzymol., 306: 308-328, 1999.

Mackey, D., and Sugden, B. The Linking Regions of EBNA1 Are Essential for Its Support of Replication and Transcription. Mol. Cell. Biol., 19: 3349-3359, 1999.

Aiyar, A., and Sugden, B. Fusions between EBNA-1 of EBV and the Large T-Antigen of SV40 Replicate Their Cognate Origins. J. Biol. Chem., 273: 33073-33081, 1998.

Aiyar, A., Tyree, C., and Sugden, B. The Plasmid Replicon of EBV Consists of Multiple cis-Acting Elements That Facilitate DNA Synthesis by the Cell and a Viral Maintenance Element. EMBO J., 17: 6394-6403, 1998.

Kirchmaier, A. L., and Sugden, B. Rep*: a Viral Element That Can Partially Replace the Origin of Plasmid DNA Synthesis of Epstein-Barr Virus. J. Virol., 72: 4657-4666, 1998.

Kirchmaier, A., and Sugden, B. Dominant-Negative Inhibitors of EBNA-1 of Epstein-Barr Virus. J. Virol., 71: 1766-1775, 1997.

Sandberg, M., Hammerschmidt, W., and Sugden, B. Characterization of the LMP-1's Association with TRAF1, TRAF2, and TRAF3. J. Virol., 71: 4649-4656, 1997.

Mackey, D., Middleton, T., and Sugden, B. Multiple Regions Within EBNA1 Can Link DNAs. J. Virol., 69: 6199-6208, 1995.

Mitchell, T., and Sugden, B. Stimulation of NF-kB-mediated Transcription by Mutant Derivatives of the Latent Membrane Protein of Epstein-Barr Virus. J. Virol., 69: 2968-2976, 1995.