Photo of James A. DeCaprio,  MD

James A. DeCaprio, MD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-3825
Fax: (617) 582-8601


james_decaprio@dfci.harvard.edu

James A. DeCaprio, MD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Active Staff and Physician, Medicine, Brigham And Women's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

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.

Publications

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  • Fischer M, DeCaprio JA. Does Arabidopsis thaliana DREAM of cell cycle control? EMBO J 2015. PubMed
  • Spurgeon ME, Cheng J, Bronson RT, Lambert PF, DeCaprio JA. Tumorigenic activity of merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice. Cancer Res 2015; 75:1068-79. PubMed
  • Berrios C, Jung J, Primi B, Wang M, Pedamallu C, Duke F, Marcelus C, Cheng J, Garcea RL, Meyerson M, DeCaprio JA. Malawi polyomavirus is a prevalent human virus that interacts with known tumor suppressors. J Virol 2014. PubMed
  • Smith JA, Haberstroh FS, White EA, Livingston DM, DeCaprio JA, Howley PM. SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter. Virology 2014; 468-470C:311-21. PubMed
  • DeCaprio JA, Duensing A. The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors. Curr Opin Oncol 2014; 26:415-21. PubMed
  • Naetar N, Soundarapandian V, Litovchick L, Goguen KL, Sablina AA, Bowman-Colin C, Sicinski P, Hahn WC, DeCaprio JA, Livingston DM. PP2A-mediated regulation of Ras signaling in G2 is essential for stable quiescence and normal G1 length. Mol Cell 2014. PubMed
  • Forristal C, Henley SA, MacDonald JI, Bush JR, Ort C, Passos DT, Talluri S, Ishak CA, Thwaites MJ, Norley CJ, Litovchick L, DeCaprio JA, DiMattia G, Holdsworth DW, Beier F, Dick FA. Loss of the mammalian DREAM complex deregulates chondrocyte proliferation. Mol Cell Biol 2014. PubMed
  • Orzalli MH, Conwell SE, Berrios C, DeCaprio JA, Knipe DM. Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA. Proc Natl Acad Sci U S A 2013; 110:E4492-501. PubMed
  • Ivanova T, Alves-Rodrigues I, Gómez-Escoda B, Dutta C, DeCaprio JA, Rhind N, Hidalgo E, Ayté J. The DNA damage and the DNA replication checkpoints converge at the MBF transcription factor. Mol Biol Cell 2013; 24:3350-7. PubMed
  • Boichuk S, Parry JA, Makielski KR, Litovchick L, Baron JL, Zewe JP, Wozniak A, Mehalek KR, Korzeniewski N, Seneviratne DS, Schöffski P, Debiec-Rychter M, DeCaprio JA, Duensing A. The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis. Cancer Res 2013; 73:5120-9. PubMed
  • Sadasivam S, DeCaprio JA. The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat Rev Cancer 2013; 13:585-95. PubMed
  • Cheng J, Rozenblatt-Rosen O, Paulson KG, Nghiem P, DeCaprio JA. Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities. J Virol 2013. PubMed
  • DeCaprio JA, Garcea RL. A cornucopia of human polyomaviruses. Nat Rev Microbiol 2013; 11:264-76. PubMed
  • Rodig SJ, Cheng J, Wardzala J, DoRosario A, Scanlon JJ, Laga AC, Martinez-Fernandez A, Barletta JA, Bellizzi AM, Sadasivam S, Holloway DT, Cooper DJ, Kupper TS, Wang LC, DeCaprio JA. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest 2012; 122:4645-53. PubMed
  • Duda DM, Olszewski JL, Tron AE, Hammel M, Lambert LJ, Waddell MB, Mittag T, DeCaprio JA, Schulman BA. Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Mol Cell 2012; 47:371-82. PubMed
  • 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; 487:491-5. PubMed
  • Min SH, Lau AW, Lee TH, Inuzuka H, Wei S, Huang P, Shaik S, Lee DY, Finn G, Balastik M, Chen CH, Luo M, Tron AE, Decaprio JA, Zhou XZ, Wei W, Lu KP. Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol Cell 2012; 46:771-83. PubMed
  • Tron AE, Arai T, Duda DM, Kuwabara H, Olszewski JL, Fujiwara Y, Bahamon BN, Signoretti S, Schulman BA, DeCaprio JA. The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7. Mol Cell 2012. PubMed
  • Sadasivam S, Duan S, DeCaprio JA. The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev 2012; 26:474-89. PubMed
  • Müller GA, Quaas M, Schümann M, Krause E, Padi M, Fischer M, Litovchick L, DeCaprio JA, Engeland K. The CHR promoter element controls cell cycle-dependent gene transcription and binds the DREAM and MMB complexes. Nucleic Acids Res 2012; 40:1561-78. PubMed
  • Gulbahce N, Yan H, Dricot A, Padi M, Byrdsong D, Franchi R, Lee DS, Rozenblatt-Rosen O, Mar JC, Calderwood MA, Baldwin A, Zhao B, Santhanam B, Braun P, Simonis N, Huh KW, Hellner K, Grace M, Chen A, Rubio R, Marto JA, Christakis NA, Kieff E, Roth FP, Roecklein-Canfield J, Decaprio JA, Cusick ME, Quackenbush J, Hill DE, Münger K, Vidal M, Barabási AL. Viral perturbations of host networks reflect disease etiology. PLoS Comput. Biol. 2012; 8:e1002531. PubMed
  • Fine DA, Rozenblatt-Rosen O, Padi M, Korkhin A, James RL, Adelmant G, Yoon R, Guo L, Berrios C, Zhang Y, Calderwood MA, Velmurgan S, Cheng J, Marto JA, Hill DE, Cusick ME, Vidal M, Florens L, Washburn MP, Litovchick L, DeCaprio JA. Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor. PLoS Pathog. 2012; 8:e1002949. PubMed
  • Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev 2011; 25:801-13. PubMed
  • Tschöp K, Conery AR, Litovchick L, Decaprio JA, Settleman J, Harlow E, Dyson N. A kinase shRNA screen links LATS2 and the pRB tumor suppressor. Genes Dev 2011; 25:814-30. PubMed
  • Gao D, Wan L, Inuzuka H, Berg AH, Tseng A, Zhai B, Shaik S, Bennett E, Tron AE, Gasser JA, Lau A, Gygi SP, Harper JW, DeCaprio JA, Toker A, Wei W. Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction. Mol Cell 2010; 39:797-808. PubMed
  • Cheng J, DeCaprio JA, Fluck MM, Schaffhausen BS. Cellular transformation by Simian Virus 40 and Murine Polyoma Virus T antigens. Semin Cancer Biol 2009; 19:218-28. PubMed
  • DeCaprio JA. Does detection of Merkel cell polyomavirus in Merkel cell carcinoma provide prognostic information? Journal of the National Cancer Institute 2009; 101:905-7. PubMed
  • Harsha HC,Kandasamy K,Ranganathan P,Rani S,Ramabadran S,Gollapudi S,Balakrishnan L,Dwivedi SB,Telikicherla D,Selvan LD,Goel R,Mathivanan S,Marimuthu A,Kashyap M,Vizza RF,Mayer RJ,Decaprio JA,Srivastava S,Hanash SM,Hruban RH,Pandey A. A compendium of potential biomarkers of pancreatic cancer. PLoS Med 2009; 6:e1000046. PubMed
  • DeCaprio JA. How the Rb tumor suppressor structure and function was revealed by the study of Adenovirus and SV40. Virology 2009; 384:274-84. PubMed
  • Kundu ST,Gosavi P,Khapare N,Patel R,Hosing AS,Maru GB,Ingle A,Decaprio JA,Dalal SN. Plakophilin3 downregulation leads to a decrease in cell adhesion and promotes metastasis. Int J Cancer 2008; 123:2303-14. PubMed
  • Borger DR, Gavrilescu LC, Bucur MC, Ivan M, Decaprio JA. AMP-activated protein kinase is essential for survival in chronic hypoxia. Biochem Biophys Res Commun 2008; 370:230-4. PubMed
  • Tsutsumi T, Kuwabara H, Arai T, Xiao Y, Decaprio JA. Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice. Mol Cell Biol 2007; 28:743-51. PubMed
  • Garneski KM,DeCaprio JA,Nghiem P. Does a new polyomavirus contribute to Merkel cell carcinoma? Genome Biol 2008; 9:228. PubMed
  • Sablina AA, Chen W, Arroyo JD, Corral L, Hector M, Bulmer SE, Decaprio JA, Hahn WC. The Tumor Suppressor PP2A Abeta Regulates the RalA GTPase. Cell 2007; 129:969-982. PubMed
  • Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, Decaprio JA. Evolutionarily Conserved Multisubunit RBL2/p130 and E2F4 Protein Complex Represses Human Cell Cycle-Dependent Genes in Quiescence. Mol Cell 2007; 26:539-51. PubMed
  • Skaar JR, Florens L, Tsutsumi T, Arai T, Tron A, Swanson SK, Washburn MP, DeCaprio JA. PARC and CUL7 form atypical cullin RING ligase complexes. Cancer Res 2007; 67:2006-14. PubMed
  • Kasper JS, Arai T, Decaprio JA. A novel p53-binding domain in CUL7. Biochem Biophys Res Commun 2006; 348:132-8. PubMed
  • Poulin DL, DeCaprio JA. Is there a role for SV40 in human cancer? J Clin Oncol 2006; 24:4356-65. PubMed
  • Poulin DL, DeCaprio JA. The carboxyl-terminal domain of large T antigen rescues SV40 host range activity in trans independent of acetylation. Virology 2006; 349:212-21. PubMed
  • Borger DR, DeCaprio JA. Targeting of p300/CREB binding protein coactivators by simian virus 40 is mediated through p53. J Virol 2006; 80:4292-303. PubMed
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