HMS Virology

Virology Faculty Member - Elliott Kieff

Elliott Kieff

Professor of Medicine

Dana-Farber Cancer Institute
450 Brookline Ave.
Mayer Bldg., Rm. 440
Boston, MA 02115
Tel: 617-632-3825
Fax: 617-582-8601
Email: james_decaprio@dfci.harvard.edu
Lab Members: 2 postdoctoral fellows, 6 graduate students



The DeCaprio Lab focuses on the discovery of fundamental biological processes that when perturbed by polyomaviruses contribute to cancer. We study viral-host cell protein interactions combined with integrative genomics to understand the contribution of Merkel cell polyomavirus to the highly aggressive Merkel cell carcinoma skin cancer.

The role of Merkel cell polyomavirus in Merkel cell carcinoma:

Merkel cell carcinoma is a skin cancer with a high rate of mortality. Factors that increase the risk for developing MCC include excessive exposure to sunlight, advanced age and an immunocompromised state. Recognition that immunodeficiency increased the risk for developing Merkel cell carcinoma prompted a focused search for pathogens and the discovery of Merkel cell polyomavirus. In at least 80% of all Merkel cell carcinomas, the Merkel cell polyomavirus small T antigen (ST) is intact, while the large T antigen (LT) is truncated. Given our laboratory’s experience in studying polyomaviruses especially SV40, we initiated studies of Merkel cell polyomavirus LT and ST. We generated monoclonal antibodies specific for LT and ST that had improved specificity and sensitivity for immunohistochemical detection of MCPyV in MCC tumor specimens that indicated that most cases of Merkel cell carcinoma express the viral T antigens. We generated a mouse knock-in model capable of tissue specific expression of the Merkel virus T antigens and demonstrated their oncogenic potential in vivo. We continue to use advanced proteomics, genomics and bioinformatic approaches to identify the tumorigenic properties of the Merkel cell polyomavirus T antigens in patient samples, mouse models and cell lines.


The DREAM (DP, RB-related, E2F and MuvB) complex:

Our laboratory demonstrated that the Retinoblastoma-related proteins p130 and p107 provide tumor suppressor activities. To determine how p130 contributed to growth suppression, we performed a large-scale immunoprecipitation followed by mass spectrometric identification of associated proteins. We identified an 8-protein complex that we termed DREAM based on its similarity to complexes previously identified by genetic and biochemical studies in C. elegans and D. melanogaster. We determined that the mammalian DREAM complex bound specifically to the promoters of all cell cycle regulated genes and repressed their expression during cellular quiescence. We determined that the DYRK1A kinase was required for assembly of the DREAM complex during quiescence. We also found that the DREAM complex underwent a metamorphosis during cell cycle progression with the MuvB component being released from p130, E2F4 and DP1 during the G1 phase of the cell cycle and subsequently binding to B-MYB (MYBL2) and FOXM1 to specifically activate expression of several hundred genes required for progression during G2 and M phase. Our work demonstrated that the DREAM complex serves as a master coordinator of cell cycle gene expression. We continue to study the DREAM complex to understand how cell cycle dependent gene expression is controlled during the major transition phases of the cell cycle including G0, G1/S and G2/M.

Identification of human disease genes by study of Viral protein-Host cell protein interactions:

Our laboratory identified CUL7, CUL9, FBXW8, GLMN and FAM111A as specific interacting proteins with SV40 LT and generated knockout mouse models for Cul7, Fbxw8, Cul9 and Glmn genes. We demonstrated that knockout of Cul7 or Fbxw8 led to severe growth retardation that was recognized by an independent genetic study that determined that homozygous mutations in CUL7 were responsible for the human 3M short stature syndrome. We demonstrated that GLMN binds directly to RBX1 and inhibits the ubiquitin ligase activity of cullin RING ligases and revealed the molecular basis for Glomuvenous malformation, a human hereditary vascular malformation syndrome. Most recently, we identified FAM111A as an SV40 host range restriction factor. Remarkably, mutations in FAM111A have recently been described in the short stature Kenny-Caffey and osteocraniostenosis syndromes. These studies of viral-host cell protein interactions have led to the molecular characterization of genes that are mutated in a variety of human diseases and suggest that LT targets cellular and organismal growth-promoting activities. Our laboratory focuses on deciphering the molecular functions of these viral-targeted host genes. We have performed a large-scale viral interactome and transcriptome screen that has fueled several new research projects and are actively pursuing new viral protein interactions with other disease related genes in addition to FAM111A and GLMN.



Last Update: 8/24/2015



Publications

1. Zhao B, Barrera LA, Ersing I, Willox B, Schmidt SC, Greenfeld H, Zhou H, Mollo SB, Shi TT, Takasaki K, Jiang S, Cahir-McFarland E, Kellis M, Bulyk ML, Kieff E, Gewurz BE. The NF-?B Genomic Landscape in Lymphoblastoid B Cells. Cell Rep. 2014 Sep 11; 8(5):1595-606.
View in: PubMed
2. Lee EK, Kim SY, Noh KW, Joo EH, Zhao B, Kieff E, Kang MS. Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome. Antiviral Res. 2014 Apr; 104:73-83.
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3. Jiang S, Willox B, Zhou H, Holthaus AM, Wang A, Shi TT, Maruo S, Kharchenko PV, Johannsen EC, Kieff E, Zhao B. Epstein-Barr Virus Nuclear Antigen 3C binds to BATF/IRF4 or SPI1/IRF4 composite sites and recruits Sin3A to repress CDKN2A. Proc Natl Acad Sci U S A. 2014 Jan 7; 111(1):421-6.
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4. Chen YL, Liu CD, Cheng CP, Zhao B, Hsu HJ, Shen CL, Chiu SJ, Kieff E, Peng CW. Nucleolin is important for Epstein-Barr virus nuclear antigen 1-mediated episome binding, maintenance, and transcription. Proc Natl Acad Sci U S A. 2014 Jan 7; 111(1):243-8.
View in: PubMed
5. Kim JE, Kim SY, Lim SY, Kieff E, Song YJ. Role of Ca2+/Calmodulin-Dependent Kinase II-IRAK1 Interaction in LMP1-Induced NF-?B Activation. Mol Cell Biol. 2014 Feb; 34(3):325-34.
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6. Portal D, Zhou H, Zhao B, Kharchenko PV, Lowry E, Wong L, Quackenbush J, Holloway D, Jiang S, Lu Y, Kieff E. Epstein-Barr virus nuclear antigen leader protein localizes to promoters and enhancers with cell transcription factors and EBNA2. Proc Natl Acad Sci U S A. 2013 Nov 12; 110(46):18537-42.
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7. Zhou X, Gewurz BE, Ritchie JM, Takasaki K, Greenfeld H, Kieff E, Davis BM, Waldor MK. A Vibrio parahaemolyticus T3SS effector mediates pathogenesis by independently enabling intestinal colonization and inhibiting TAK1 activation. Cell Rep. 2013 May 30; 3(5):1690-702.
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8. Liu CD, Cheng CP, Fang JS, Chen LC, Zhao B, Kieff E, Peng CW. Modulation of Epstein-Barr virus nuclear antigen 2-dependent transcription by protein arginine methyltransferase 5. Biochem Biophys Res Commun. 2013 Jan 18; 430(3):1097-102.
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9. Liu CD, Chen YL, Min YL, Zhao B, Cheng CP, Kang MS, Chiu SJ, Kieff E, Peng CW. The nuclear chaperone nucleophosmin escorts an Epstein-Barr Virus nuclear antigen to establish transcriptional cascades for latent infection in human B cells. PLoS Pathog. 2012; 8(12):e1003084.
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10. Rozenblatt-Rosen O, Deo RC, Padi M, Adelmant G, Calderwood MA, Rolland T, Grace M, Dricot A, Askenazi M, Tavares M, Pevzner SJ, Abderazzaq F, Byrdsong D, Carvunis AR, Chen AA, Cheng J, Correll M, Duarte M, Fan C, Feltkamp MC, Ficarro SB, Franchi R, Garg BK, Gulbahce N, Hao T, Holthaus AM, James R, Korkhin A, Litovchick L, Mar JC, Pak TR, Rabello S, Rubio R, Shen Y, Singh S, Spangle JM, Tasan M, Wanamaker S, Webber JT, Roecklein-Canfield J, Johannsen E, Barabási AL, Beroukhim R, Kieff E, Cusick ME, Hill DE, Münger K, Marto JA, Quackenbush J, Roth FP, DeCaprio JA, Vidal M. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature. 2012 Jul 26; 487(7408):491-5.
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11. Kim SY, Song KA, Kieff E, Kang MS. Small molecule and peptide-mediated inhibition of Epstein-Barr virus nuclear antigen 1 dimerization. Biochem Biophys Res Commun. 2012 Jul 27; 424(2):251-6.
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12. Gewurz BE, Towfic F, Mar JC, Shinners NP, Takasaki K, Zhao B, Cahir-McFarland ED, Quackenbush J, Xavier RJ, Kieff E. Genome-wide siRNA screen for mediators of NF-?B activation. Proc Natl Acad Sci U S A. 2012 Feb 14; 109(7):2467-72.
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13. Geiser V, Cahir-McFarland E, Kieff E. Latent membrane protein 1 is dispensable for Epstein-Barr virus replication in human embryonic kidney 293 cells. PLoS One. 2011; 6(8):e22929.
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14. Zhao B, Zou J, Wang H, Johannsen E, Peng CW, Quackenbush J, Mar JC, Morton CC, Freedman ML, Blacklow SC, Aster JC, Bernstein BE, Kieff E. Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. Proc Natl Acad Sci U S A. 2011 Sep 6; 108(36):14902-7.
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15. Wang H, Zou J, Zhao B, Johannsen E, Ashworth T, Wong H, Pear WS, Schug J, Blacklow SC, Arnett KL, Bernstein BE, Kieff E, Aster JC. Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. Proc Natl Acad Sci U S A. 2011 Sep 6; 108(36):14908-13.
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16. Xing L, Kieff E. cis-Acting effects on RNA processing and Drosha cleavage prevent Epstein-Barr virus latency III BHRF1 expression. J Virol. 2011 Sep; 85(17):8929-39.
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17. Gewurz BE, Mar JC, Padi M, Zhao B, Shinners NP, Takasaki K, Bedoya E, Zou JY, Cahir-McFarland E, Quackenbush J, Kieff E. Canonical NF-kappaB activation is essential for Epstein-Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation. J Virol. 2011 Jul; 85(13):6764-73.
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18. Verweij FJ, van Eijndhoven MA, Hopmans ES, Vendrig T, Wurdinger T, Cahir-McFarland E, Kieff E, Geerts D, van der Kant R, Neefjes J, Middeldorp JM, Pegtel DM. LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-?B activation. EMBO J. 2011 Jun 1; 30(11):2115-29.
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19. Portal D, Zhao B, Calderwood MA, Sommermann T, Johannsen E, Kieff E. EBV nuclear antigen EBNALP dismisses transcription repressors NCoR and RBPJ from enhancers and EBNA2 increases NCoR-deficient RBPJ DNA binding. Proc Natl Acad Sci U S A. 2011 May 10; 108(19):7808-13.
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20. Calderwood MA, Lee S, Holthaus AM, Blacklow SC, Kieff E, Johannsen E. Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Virology. 2011 May 25; 414(1):19-25.
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21. Maruo S, Zhao B, Johannsen E, Kieff E, Zou J, Takada K. Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci U S A. 2011 Feb 1; 108(5):1919-24.
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22. Kang MS, Lee EK, Soni V, Lewis TA, Koehler AN, Srinivasan V, Kieff E. Roscovitine inhibits EBNA1 serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance. J Virol. 2011 Mar; 85(6):2859-68.
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23. Zhao B, Mar JC, Maruo S, Lee S, Gewurz BE, Johannsen E, Holton K, Rubio R, Takada K, Quackenbush J, Kieff E. Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines. Proc Natl Acad Sci U S A. 2011 Jan 4; 108(1):337-42.
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24. Boehm D, Gewurz BE, Kieff E, Cahir-McFarland E. Epstein-Barr latent membrane protein 1 transformation site 2 activates NF-kappaB in the absence of NF-kappaB essential modifier residues 133-224 or 373-419. Proc Natl Acad Sci U S A. 2010 Oct 19; 107(42):18103-8.
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25. Lee S, Sakakibara S, Maruo S, Zhao B, Calderwood MA, Holthaus AM, Lai CY, Takada K, Kieff E, Johannsen E. Epstein-Barr virus nuclear protein 3C domains necessary for lymphoblastoid cell growth: interaction with RBP-Jkappa regulates TCL1. J Virol. 2009 Dec; 83(23):12368-77.
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26. Maruo S, Wu Y, Ito T, Kanda T, Kieff ED, Takada K. Epstein-Barr virus nuclear protein EBNA3C residues critical for maintaining lymphoblastoid cell growth. Proc Natl Acad Sci U S A. 2009 Mar 17; 106(11):4419-24.
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27. Fernandez AF, Rosales C, Lopez-Nieva P, Graña O, Ballestar E, Ropero S, Espada J, Melo SA, Lujambio A, Fraga MF, Pino I, Javierre B, Carmona FJ, Acquadro F, Steenbergen RD, Snijders PJ, Meijer CJ, Pineau P, Dejean A, Lloveras B, Capella G, Quer J, Buti M, Esteban JI, Allende H, Rodriguez-Frias F, Castellsague X, Minarovits J, Ponce J, Capello D, Gaidano G, Cigudosa JC, Gomez-Lopez G, Pisano DG, Valencia A, Piris MA, Bosch FX, Cahir-McFarland E, Kieff E, Esteller M. The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Res. 2009 Mar; 19(3):438-51.
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28. Choy E, Yelensky R, Bonakdar S, Plenge RM, Saxena R, De Jager PL, Shaw SY, Wolfish CS, Slavik JM, Cotsapas C, Rivas M, Dermitzakis ET, Cahir-McFarland E, Kieff E, Hafler D, Daly MJ, Altshuler D. Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet. 2008 Nov; 4(11):e1000287.
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29. Song YJ, Izumi KM, Shinners NP, Gewurz BE, Kieff E. IRF7 activation by Epstein-Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3. Proc Natl Acad Sci U S A. 2008 Nov 25; 105(47):18448-53.
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30. Kang MS, Soni V, Bronson R, Kieff E. Epstein-Barr virus nuclear antigen 1 does not cause lymphoma in C57BL/6J mice. J Virol. 2008 Apr; 82(8):4180-3.
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