Photo of Kenneth M. Kaye,  MD

Kenneth M. Kaye, MD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-4256
Fax: (617) 525-4251


kkaye@rics.bwh.harvard.edu

Kenneth M. Kaye, MD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Associate Physician, Channing Laboratory, Brigham And Women's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory investigates the link between herpesviruses and human malignancy. Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is linked with Kaposi's sarcoma, body cavity-based lymphomas and multicentric Castleman's disease, a lymphoproliferative disorder. Our goal is to gain a better understanding of the molecular mechanisms by which KSHV exerts tumorigenic effects.


KSHV infection in tumor cells is primarily latent. In latently infected cells, KSHV persists as a multiple copy plasmid (episome). In order to persist in proliferating cells, KSHV episomes must replicate and efficiently segregate to progeny cells. The KSHV latency-associated nuclear antigen (LANA) is expressed in KSHV infected tumor cells. We have shown that LANA colocalizes with KSHV episomes on chromosomes of KSHV infected cells. In addition, LANA is necessary and sufficient to mediate persistence of episomal DNA containing a specific KSHV sequence. These data are consistent with a model in which LANA tethers KSHV episomes to chromosomes during mitosis to ensure efficient segregation of KSHV DNA to progeny cells. We are presently investigating the molecular mechanisms by which LANA serves this function.

Publications

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  • Beauchemin C, Moerke NJ, Faloon P, Kaye KM. Assay Development and High-Throughput Screening for Inhibitors of Kaposi's Sarcoma-Associated Herpesvirus N-Terminal Latency-Associated Nuclear Antigen Binding to Nucleosomes. J Biomol Screen 2014. PubMed
  • De León Vázquez E, Juillard F, Rosner B, Kaye KM. A short sequence immediately upstream of the internal repeat elements is critical for KSHV LANA mediated DNA replication and impacts episome persistence. Virology 2013; 448:344-55. PubMed
  • Vázquez Ede L, Carey VJ, Kaye KM. Identification of Kaposi's sarcoma-associated herpesvirus LANA regions important for episome segregation, replication, and persistence. J Virol 2013; 87:12270-83. PubMed
  • Correia B, Cerqueira SA, Beauchemin C, Pires de Miranda M, Li S, Ponnusamy R, Rodrigues L, Schneider TR, Carrondo MA, Kaye KM, Simas JP, McVey CE. Crystal structure of the gamma-2 herpesvirus LANA DNA binding domain identifies charged surface residues which impact viral latency. PLoS Pathog. 2013; 9:e1003673. PubMed
  • Rodrigues L, Popov N, Kaye KM, Simas JP. Stabilization of Myc through heterotypic poly-ubiquitination by mLANA is critical for 粒-herpesvirus lymphoproliferation. PLoS Pathog. 2013; 9:e1003554. PubMed
  • Habison AC, Beauchemin C, Simas JP, Usherwood EJ, Kaye KM. Murine Gammaherpesvirus 68 LANA Acts on Terminal Repeat DNA To Mediate Episome Persistence. J Virol 2012; 86:11863-76. PubMed
  • Pogue JM, Potoski BA, Kaye KS. Aminoglycoside use in intensive care units and aminoglycoside nephrotoxicity. Comment letter 1. Antimicrob Agents Chemother 2010; 54:2750, author reply 2751. PubMed
  • Kelley-Clarke B,De Leon-Vazquez E,Slain K,Barbera AJ,Kaye KM. Role of Kaposi's sarcoma-associated herpesvirus C-terminal LANA chromosome binding in episome persistence. J Virol 2009; 83:4326-37. PubMed
  • Chodaparambil JV, Barbera AJ, Lu X, Kaye KM, Hansen JC, Luger K. A charged and contoured surface on the nucleosome regulates chromatin compaction. Nat Struct Mol Biol 2007; 14:1105-7. PubMed
  • Bihl F, Narayan M, Chisholm JV, Henry LM, Suscovich TJ, Brown EE, Welzel TM, Kaufmann DE, Zaman TM, Dollard S, Martin JN, Wang F, Scadden DT, Kaye KM, Brander C. Lytic and latent antigens of the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus induce T-cell responses with similar functional properties and memory phenotypes. J Virol 2007; 81:4904-8. PubMed
  • Kelley-Clarke B, Ballestas ME, Srinivasan V, Barbera AJ, Komatsu T, Harris TA, Kazanjian M, Kaye KM. Determination of Kaposi's sarcoma-associated herpesvirus C-terminal latency-associated nuclear antigen residues mediating chromosome association and DNA binding. J Virol 2007; 81:4348-56. PubMed
  • Kelley-Clarke B, Ballestas ME, Komatsu T, Kaye KM. Kaposi's sarcoma herpesvirus C-terminal LANA concentrates at pericentromeric and peri-telomeric regions of a subset of mitotic chromosomes. Virology 2006; 357:149-57. PubMed
  • You J, Srinivasan V, Denis GV, Harrington WJ, Ballestas ME, Kaye KM, Howley PM. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol 2006; 80:8909-19. PubMed
  • Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Luger K, Kaye KM. Kaposi's sarcoma-associated herpesvirus LANA hitches a ride on the chromosome. Cell Cycle 2006; 5:1048-52. PubMed
  • Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Joukov V, Walter JC, Luger K, Kaye KM. The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science 2006; 311:856-61. PubMed
  • Komatsu T, Ballestas ME, Barbera AJ, Kelley-Clarke B, Kaye KM. KSHV LANA1 binds DNA as an oligomer and residues N-terminal to the oligomerization domain are essential for DNA binding, replication, and episome persistence. Virology 2004; 319:225-36. PubMed
  • Barbera AJ, Ballestas ME, Kaye KM. The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 N terminus is essential for chromosome association, DNA replication, and episome persistence. J Virol 2003; 78:294-301. PubMed
  • Li H, Komatsu T, Dezube BJ, Kaye KM. The Kaposi's sarcoma-associated herpesvirus K12 transcript from a primary effusion lymphoma contains complex repeat elements, is spliced, and initiates from a novel promoter. J Virol 2002; 76:11880-8. PubMed
  • Ballestas ME, Kaye KM. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mediates episome persistence through cis-acting terminal repeat (TR) sequence and specifically binds TR DNA. J Virol 2001; 75:3250-8. PubMed
  • Komatsu T, Barbera AJ, Ballestas ME, Kaye KM. The Kaposi' s sarcoma-associated herpesvirus latency-associated nuclear antigen. Viral Immunol 2002; 14:311-7. PubMed
  • Fisman DN, Kaye KM. Once-daily dosing of aminoglycoside antibiotics. Infect Dis Clin North Am 2000; 14:475-87. PubMed
  • Ballestas ME, Chatis PA, Kaye KM. Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 1999; 284:641-4. PubMed
  • Jones D, Ballestas ME, Kaye KM, Gulizia JM, Winters GL, Fletcher J, Scadden DT, Aster JC. Primary-effusion lymphoma and Kaposi's sarcoma in a cardiac-transplant recipient. N Engl J Med 1998; 339:444-9. PubMed
  • Eliopoulos AG, Stack M, Dawson CW, Kaye KM, Hodgkin L, Sihota S, Rowe M, Young LS. Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappaB pathway involving TNF receptor-associated factors. Oncogene 1997; 14:2899-916. PubMed
  • Devergne O, Hatzivassiliou E, Izumi KM, Kaye KM, Kleijnen MF, Kieff E, Mosialos G. Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation. Mol Cell Biol 1996; 16:7098-108. PubMed
  • Ansieau S, Scheffrahn I, Mosialos G, Brand H, Duyster J, Kaye K, Harada J, Dougall B, H. Tumor necrosis factor receptor-associated factor (TRAF)-1, TRAF-2, and TRAF-3 interact in vivo with the CD30 cytoplasmic domain; TRAF-2 mediates CD30-induced nuclear factor kappa B activation. Proc Natl Acad Sci U S A 1996; 93:14053-8. PubMed
  • Kaye KM, Izumi KM, Mosialos G, Kieff E. The Epstein-Barr virus LMP1 cytoplasmic carboxy terminus is essential for B-lymphocyte transformation; fibroblast cocultivation complements a critical function within the terminal 155 residues. J Virol 1995; 69:675-83. PubMed
  • Izumi KM, Kaye KM, Kieff ED. Epstein-Barr virus recombinant molecular genetic analysis of the LMP1 amino-terminal cytoplasmic domain reveals a probable structural role, with no component essential for primary B-lymphocyte growth transformation. J Virol 1994; 68:4369-76. PubMed
  • Kaye KM, Izumi KM, Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A 1993; 90:9150-4. PubMed
  • Kaye KM, Spriggs DR, Bassel-Duby R, Fields BN, Tyler KL. Genetic basis for altered pathogenesis of an immune-selected antigenic variant of reovirus type 3 (Dearing). J Virol 1986; 59:90-7. PubMed
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