Nuclear Factor kappa B is central to Marek’s Disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo

BMC Systems Biology

Shane C Burgess¹  Hans H Cheng¹  Ken Pendarvis⁶  Sugalesini Subramaniam⁷  Huaijun Zhou³  Hsin-I Chiang⁴  Joram J Buza⁵  Dusan Kunec⁸  Shyamesh Kumar² 

[1] USDA-ARS, Avian Disease and Oncology Laboratory, 4279 East Mount Hope Road, East Lansing, MI, 48823, USA;Department of Pathobiology and Population Medicine, Mississippi State University, PO Box 6100, MS, Mississippi State, 39762, USA;Department of Poultry Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, 77843, USA;Department of Bioengineering, University of California-San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA;School of Life Sciences and Bioengineering, Nelson Mandela African Institute of Science and Technology, PO Box 447, Arusha, Tanzania;College of Agriculture and Life Sciences, University of Arizona, P.O. Box 210036, Tucson, AZ, 85721, USA;Comparative Medicine and Integrative Biology Graduate Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI, 48824, USA;Institut für Virologie, Freie Universität Berlin, Berlin, Germany

关键词: Proteomics;    CD30;    Genetic resistance;    NF-κB;    Meq;    Lymphomas;    Marek’s disease;   

Others  :  1143601
DOI  :  10.1186/1752-0509-6-123

 received in 2012-06-13, accepted in 2012-09-04,  发布年份 2012

【 摘 要 】

Background

Marek’s Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30^hi) and are in minority, while the non-neoplastic cells (CD30^lo) form the majority of population. MD is a unique natural in-vivo model of human CD30^hi lymphomas with both natural CD30^hi lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30^lo expressing phenotype to CD30^hi expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30^lo and CD30^hi cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome.

Results

Our results show that a) CD30^lo lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes; b) multiple transformation mechanisms exist and are potentially controlled by Meq; c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-κB, and, in turn, increases Meq transcription; d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis.

Conclusions

In the context of the MD lymphoma microenvironment (and potentially in other CD30^hi lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor cells and not merely immune bystanders. We also show that NF-κB is a central player in MDV induced neoplastic transformation of CD30-expressing lymphocytes in vivo. Our results provide insights into molecular mechanisms of neoplastic transformation in MD specifically and also herpesvirus induced lymphoma in general.

【 授权许可】

   
2012 Kumar et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Felberbaum RS: The molecular mechanisms of classic Hodgkin's lymphoma. Yale J Biol Med 2005, 78:203-210.
• [2]Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43-66.
• [3]Buza JJ, Burgess SC: Modeling the proteome of a Marek's disease transformed cell line: a natural animal model for CD30 overexpressing lymphomas. Proteomics 2007, 7:1316-1326.
• [4]Willemze R, Beljaards RC: Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 1993, 28:973-980.
• [5]Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, Diaz-Perez JL, Geerts ML, Goos M, Knobler R, et al.: EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 1997, 90:354-371.
• [6]Kumar S: Buza JJ. Genotype-Dependent Tumor Regression in Marek's Disease Mediated at the Level of Tumor Immunity. Cancer Microenviron, Burgess SC; 2009.
• [7]Burgess SC: Marek's Disease Lymphomas. In Marek's Disease An Evolving Problem. Edited by Davison F, Nair V. Oxford: Elsevier Academic Press; 2004:109. Pastoret P-P (Series Editor)
• [8]Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A: The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol 2010, 221:248-263. http://www.ncbi.nlm.nih.gov/pubmed/20527019?dopt=Citation webcite
• [9]Burgess SC, Basaran BH, Davison TF: Resistance to Marek's disease herpesvirus-induced lymphoma is multiphasic and dependent on host genotype. Vet Pathol 2001, 38:129-142.
• [10]Abdulamir AS, Kadhim HS, Hafidh RR, Ali MA, Faik I, Abubakar F, Abbas KA: Severity of asthma: the role of CD25+, CD30+, NF-kappaB, and apoptotic markers. J Investig Allergol Clin Immunol 2009, 19:218-224.
• [11]Xie P, Kraus ZJ, Stunz LL, Bishop GA: Roles of TRAF molecules in B lymphocyte function. Cytokine Growth Factor Rev 2008, 19:199-207.
• [12]Shack LA, Buza JJ, Burgess SC: The neoplastically transformed (CD30(hi)) Marek's disease lymphoma cell phenotype most closely resembles T-regulatory cells. Cancer Immunol Immunother 2008, 57:1253-1262.
• [13]Gascoyne RD, Rosenwald A, Poppema S, Lenz G: Prognostic biomarkers in malignant lymphomas. Leuk Lymphoma 2010, 51(Suppl 1):11-19. http://www.ncbi.nlm.nih.gov/pubmed/20658955?dopt=Citation webcite
• [14]Herreros B, Sanchez-Aguilera A, Piris MA: Lymphoma microenvironment: culprit or innocent? Leukemia 2008, 22:49-58.
• [15]Burgess SC, Davison TF: Identification of the neoplastically transformed cells in Marek's disease herpesvirus-induced lymphomas: recognition by the monoclonal antibody AV37. J Virol 2002, 76:7276-7292.
• [16]Ghosh S, May MJ, Kopp EB: NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998, 16:225-260.
• [17]Horie R, Watanabe T, Morishita Y, Ito K, Ishida T, Kanegae Y, Saito I, Higashihara M, Mori S, Kadin ME: Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells. Oncogene 2002, 21:2493-2503.
• [18]Burgess SC, Young JR, Baaten BJ, Hunt L, Ross LN, Parcells MS, Kumar PM, Tregaskes CA, Lee LF, Davison TF: Marek's disease is a natural model for lymphomas overexpressing Hodgkin's disease antigen (CD30). Proc Natl Acad Sci USA 2004, 101:13879-13884.
• [19]Ross N, O'Sullivan G, Rothwell C, Smith G, Burgess SC, Rennie M, Lee LF, Davison TF: Marek's disease virus EcoRI-Q gene (meq) and a small RNA antisense to ICP4 are abundantly expressed in CD4+ cells and cells carrying a novel lymphoid marker, AV37, in Marek's disease lymphomas. J Gen Virol 1997, 78(Pt 9):2191-2198.
• [20]Liu JL, Kung HJ: Marek's disease herpesvirus transforming protein MEQ: a c-Jun analogue with an alternative life style. Virus Genes 2000, 21:51-64.
• [21]Brown AC, Smith LP, Kgosana L, Baigent SJ, Nair V, Allday MJ: Homodimerization of the Meq viral oncoprotein is necessary for induction of T-cell lymphoma by Marek's disease virus. J Virol 2009, 83:11142-11151.
• [22]Chen G, Gharib TG, Huang CC, Taylor JM, Misek DE, Kardia SL, Giordano TJ, Iannettoni MD, Orringer MB, Hanash SM, Beer DG: Discordant protein and mRNA expression in lung adenocarcinomas. Mol Cell Proteomics 2002, 1:304-313.
• [23]Gygi SP, Rochon Y, Franza BR, Aebersold R: Correlation between protein and mRNA abundance in yeast. Mol Cell Biol 1999, 19:1720-1730.
• [24]Hornshoj H, Bendixen E, Conley LN, Andersen PK, Hedegaard J, Panitz F, Bendixen C: Transcriptomic and proteomic profiling of two porcine tissues using high-throughput technologies. BMC Genomics 2009, 10:30. BioMed Central Full Text
• [25]Kanehisa M, Goto S, Furumichi M, Tanabe M, Hirakawa M: KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res 2010, 38:D355-D360. http://www.ncbi.nlm.nih.gov/pubmed/19880382?dopt=Citation webcite
• [26]Buza JJ, Burgess SC: Different Signaling Pathways Expressed by Chicken Naive CD4(+) T Cells, CD4(+) Lymphocytes Activated with Staphylococcal Enterotoxin B, and Those Malignantly Transformed by Marek's Disease Virus. J Proteome Res 2008, 7(6):2380-2387. Epub 2008 Apr 16 http://www.ncbi.nlm.nih.gov/pubmed/18412384 webcite
• [27]Terry KL, Tworoger SS, Gates MA, Cramer DW, Hankinson SE: Common Genetic Variation in IGF1, IGFBP1, and IGFBP3 and Ovarian Cancer Risk. Carcinogenesis 2009, 30(12):2042-2046. http://www.ncbi.nlm.nih.gov/pubmed/19858071?dopt=Citation webcite
• [28]Eleswarapu S, Ge X, Wang Y, Yu J, Jiang H: Growth hormone-activated STAT5 may indirectly stimulate IGF-I gene transcription through HNF-3{gamma}. Mol Endocrinol 2009, 23:2026-2037.
• [29]Liu HC, Kung HJ, Fulton JE, Morgan RW, Cheng HH: Growth hormone interacts with the Marek's disease virus SORF2 protein and is associated with disease resistance in chicken. Proc Natl Acad Sci USA 2001, 98:9203-9208.
• [30]Choi YL, Tsukasaki K, O'Neill MC, Yamada Y, Onimaru Y, Matsumoto K, Ohashi J, Yamashita Y, Tsutsumi S, Kaneda R, et al.: A genomic analysis of adult T-cell leukemia. Oncogene 2007, 26:1245-1255.
• [31]Onimaru Y, Tsukasaki K, Murata K, Imaizumi Y, Choi YL, Hasegawa H, Sugahara K, Yamada Y, Hayashi T, Nakashima M, et al.: Autocrine and/or paracrine growth of aggressive ATLL cells caused by HGF and c-Met. Int J Oncol 2008, 33:697-703.
• [32]Montaldo F, Maffe A, Morini M, Noonan D, Giordano S, Albini A, Prat M: Expression of functional tyrosine kinases on immortalized Kaposi's sarcoma cells. J Cell Physiol 2000, 184:246-254.
• [33]Jucker M, Gunther A, Gradl G, Fonatsch C, Krueger G, Diehl V, Tesch H: The Met/hepatocyte growth factor receptor (HGFR) gene is overexpressed in some cases of human leukemia and lymphoma. Leuk Res 1994, 18:7-16.
• [34]Wang X, DeFrances MC, Dai Y, Pediaditakis P, Johnson C, Bell A, Michalopoulos GK, Zarnegar R: A mechanism of cell survival: sequestration of Fas by the HGF receptor Met. Mol Cell 2002, 9:411-421.
• [35]Karabatsou K, Pal P, Dodd S, Mat A, Haylock B, Aguirreburualde M, Moxam N, Pinson-Ellis W, Broome J, Rainov NG: Expression of survivin, platelet-derived growth factor A (PDGF-A) and PDGF receptor alpha in primary central nervous system lymphoma. J Neurooncol 2006, 79:171-179.
• [36]Chen YP, Chang KC, Su WC, Chen TY: The expression and prognostic significance of platelet-derived growth factor receptor alpha in mature T- and natural killer-cell lymphomas. Ann Hematol 2008, 87:985-990.
• [37]Brown RE, Nazmi RK: The Reed-Steinberg cell: molecular characterization by proteomic analysis with therapeutic implications. Ann Clin Lab Sci 2002, 32:339-351.
• [38]Wang SC, Hung MC: Nuclear Translocation of the Epidermal Growth Factor Receptor Family Membrane Tyrosine Kinase Receptors. Clinical Cancer Res 2009, 15(21):6484-6489. Epub 2009 Oct 27. http://www.ncbi.nlm.nih.gov/pubmed/19861462?dopt=Citation webcite
• [39]Levy AM, Gilad O, Xia L, Izumiya Y, Choi J, Tsalenko A, Yakhini Z, Witter R, Lee L, Cardona CJ, Kung HJ: Marek's disease virus Meq transforms chicken cells via the v-Jun transcriptional cascade: a converging transforming pathway for avian oncoviruses. Proc Natl Acad Sci USA 2005, 102:14831-14836.
• [40]McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D'Assoro AB, et al.: Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 2006, 46:249-279.
• [41]Zhang S, Yu D: PI(3)king apart PTEN's role in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2010, 16:4325-4330.
• [42]Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70.
• [43]Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 1995, 81:323-330.
• [44]Polakis P: Wnt signaling and cancer. Genes Dev 2000, 14:1837-1851.
• [45]Groen RW, Oud ME, Schilder-Tol EJ, Overdijk MB, ten Berge D, Nusse R, Spaargaren M, Pals ST: Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies. Cancer Res 2008, 68:6969-6977.
• [46]Liu JL, Ye Y, Lee LF, Kung HJ: Transforming potential of the herpesvirus oncoprotein MEQ: morphological transformation, serum-independent growth, and inhibition of apoptosis. J Virol 1998, 72:388-395.
• [47]Didelot C, Schmitt E, Brunet M, Maingret L, Parcellier A, Garrido C: Heat shock proteins: endogenous modulators of apoptotic cell death. Handb Exp Pharmacol 2006, (172):171-198. http://www.ncbi.nlm.nih.gov/pubmed/16610360?dopt=Citation) webcite
• [48]Dudeja V, Mujumdar N, Phillips P, Chugh R, Borja-Cacho D, Dawra RK, Vickers SM, Saluja AK: Heat shock protein 70 inhibits apoptosis in cancer cells through simultaneous and independent mechanisms. Gastroenterology 2009, 136:1772-1782.
• [49]Zhao Y, Kurian D, Xu H, Petherbridge L, Smith LP, Hunt L, Nair V: Interaction of Marek's disease virus oncoprotein Meq with heat-shock protein 70 in lymphoid tumour cells. J Gen Virol 2009, 90:2201-2208.
• [50]Glaessgen A, Jonmarker S, Lindberg A, Nilsson B, Lewensohn R, Ekman P, Valdman A, Egevad L: Heat shock proteins 27, 60 and 70 as prognostic markers of prostate cancer. APMIS 2008, 116:888-895.
• [51]McTavish N, Copeland LA, Saville MK, Perkins ND, Spruce BA: Proenkephalin assists stress-activated apoptosis through transcriptional repression of NF-kappaB- and p53-regulated gene targets. Cell Death Differ 2007, 14:1700-1710.
• [52]Belgiovine C, Chiodi I, Mondello C: Telomerase: cellular immortalization and neoplastic transformation. Multiple functions of a multifaceted complex. Cytogenet Genome Res 2008, 122:255-262.
• [53]Baumann P, Cech TR: Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 2001, 292:1171-1175.
• [54]Pitt CW, Cooper JP: Pot1 inactivation leads to rampant telomere resection and loss in one cell cycle. Nucleic Acids Res 2010, 38(20):6968-6975. Epub 2010 Jul 3.( http://www.ncbi.nlm.nih.gov/pubmed/20601686?dopt=Citation webcite)
• [55]Shen R, Ye Y, Chen L, Yan Q, Barsky SH, Gao JX: Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS One 2008, 3:e1652.
• [56]Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, Helman LJ: The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 2004, 10:182-186.
• [57]Bruce B, Khanna G, Ren L, Landberg G, Jirstrom K, Powell C, Borczuk A, Keller ET, Wojno KJ, Meltzer P, et al.: Expression of the cytoskeleton linker protein ezrin in human cancers. Clin Exp Metastasis 2007, 24:69-78.
• [58]Bretscher A, Edwards K, Fehon RG: ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 2002, 3:586-599.
• [59]Martin TA, Harrison G, Mansel RE, Jiang WG: The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol 2003, 46:165-186.
• [60]Kang YK, Hong SW, Lee H, Kim WH: Prognostic implications of ezrin expression in human hepatocellular carcinoma. Mol Carcinog 2010, 49:798-804.
• [61]Ma PC, Maulik G, Christensen J: Salgia R: c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 2003, 22:309-325.
• [62]Long ET, Baker S, Oliveira V, Sawitzki B, Wood KJ: Alpha-1,2-mannosidase and hence N-glycosylation are required for regulatory T cell migration and allograft tolerance in mice. PLoS One 2010, 5:e8894. http://www.ncbi.nlm.nih.gov/pubmed/20126660?dopt=Citation webcite
• [63]Basler T, Jeckstadt S, Valentin-Weigand P, Goethe R: Mycobacterium paratuberculosis, Mycobacterium smegmatis, and lipopolysaccharide induce different transcriptional and post-transcriptional regulation of the IRG1 gene in murine macrophages. J Leukoc Biol 2006, 79:628-638.
• [64]Smith J, Sadeyen JR, Paton IR, Hocking PM, Salmon N, Fife M, Nair V, Burt DW, Kaiser P: Systems analysis of immune responses in Marek's disease virus-infected chickens identifies a gene involved in susceptibility and highlights a possible novel pathogenicity mechanism. J Virol 2011, 85:11146-11158.
• [65]Yu Y, Zhang H, Tian F, Zhang W, Fang H, Song J: An integrated epigenetic and genetic analysis of DNA methyltransferase genes (DNMTs) in tumor resistant and susceptible chicken lines. PLoS One 2008, 3:e2672.
• [66]Burgess SC, Davison TF: A quantitative duplex PCR technique for measuring amounts of cell-associated Marek's disease virus: differences in two populations of lymphoma cells. J Virol Methods 1999, 82:27-37.
• [67]Young LS, Murray PG: Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene 2003, 22:5108-5121.
• [68]Minarovits J: Epigenotypes of latent herpesvirus genomes. Curr Top Microbiol Immunol 2006, 310:61-80.
• [69]McCarthy FM, Mahony TJ, Parcells MS, Burgess SC: Understanding animal viruses using the Gene Ontology. Trends Microbiol 2009, 17:328-335.
• [70]Parvizi P, Andrzejewski K, Read LR, Behboudi S, Sharif S: Expression profiling of genes associated with regulatory functions of T-cell subsets in Marek's disease virus-infected chickens. Avian pathology : journal of the WVPA 2010, 39:367-373.
• [71]Chiang HI, Swaggerty CL, Kogut MH, Dowd SE, Li X, Pevzner IY, Zhou H: Gene expression profiling in chicken heterophils with Salmonella enteritidis stimulation using a chicken 44 K Agilent microarray. BMC Genomics 2008, 9:526. BioMed Central Full Text
• [72]Li X, Chiang HI, Zhu J, Dowd SE, Zhou H: Characterization of a newly developed chicken 44 K Agilent microarray. BMC Genomics 2008, 9:60. BioMed Central Full Text
• [73]Friedenson B: The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers. BMC Cancer 2007, 7:152. BioMed Central Full Text
• [74]Zhou M, Fadlelmola FM, Cohn JB, Skinnider B, Gascoyne RD, Banerjee D: Constitutive overexpression of a novel 21 kDa protein by Hodgkin lymphoma and aggressive non-Hodgkin lymphomas. Mol Cancer 2008, 7:12. BioMed Central Full Text
• [75]Voorzanger-Rousselot N, Alberti L, Blay JY: CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways. BMC Cancer 2006, 6:75. BioMed Central Full Text
• [76]Ma Y, Visser L, Roelofsen H, de Vries M, Diepstra A, van Imhoff G, van der Wal T, Luinge M, Alvarez-Llamas G, Vos H, et al.: Proteomics analysis of Hodgkin lymphoma: identification of new players involved in the cross-talk between HRS cells and infiltrating lymphocytes. Blood 2008, 111:2339-2346.
• [77]Mulaomerovic A, Halilbasic A, Cickusic E, Zavasnik-Bergant T, Begic L, Kos J: Cystatin C as a potential marker for relapse in patients with non-Hodgkin B-cell lymphoma. Cancer Lett 2007, 248:192-197.
• [78]Poteryaeva ON, Falameyeva OV, Korolenko TA, Kaledin VI, Djanayeva SJ, Nowicky JW, Sandula J: Cysteine proteinase inhibitor level in tumor and normal tissues in control and cured mice. Drugs Exp Clin Res 2000, 26:301-306.
• [79]Poteryaeva ON, Falameeva OV, Zhanaeva SY, Svechnikova IG, Korolenko TA, Kaledin VI: Role of cystatin C and cysteine proteinases in the development of mouse LS-lymphosarcoma. Bull Exp Biol Med 2001, 132:675-677.
• [80]Horie R, Higashihara M, Watanabe T: Hodgkin's lymphoma and CD30 signal transduction. Int J Hematol 2003, 77:37-47.
• [81]Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT, Ridker PM, Libby P, Chapman HA: Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 1999, 104:1191-1197.
• [82]Kos J, Stabuc B, Schweiger A, Krasovec M, Cimerman N, Kopitar-Jerala N, Vrhovec I: Cathepsins B, H, and L and their inhibitors stefin A and cystatin C in sera of melanoma patients. Clinical cancer research : an official journal of the American Association for Cancer Research 1997, 3:1815-1822.
• [83]Joyce JA, Baruch A, Chehade K, Meyer-Morse N, Giraudo E, Tsai FY, Greenbaum DC, Hager JH, Bogyo M, Hanahan D: Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 2004, 5:443-453.
• [84]Wang B, Sun J, Kitamoto S, Yang M, Grubb A, Chapman HA, Kalluri R, Shi GP: Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J Biol Chem 2006, 281:6020-6029.
• [85]Qian Z, Brunovskis P, Rauscher F 3rd: Lee L, Kung HJ: Transactivation activity of Meq, a Marek's disease herpesvirus bZIP protein persistently expressed in latently infected transformed T cells. J Virol 1995, 69:4037-4044.
• [86]Carlson JM, Chakravarty A, DeZiel CE, Gross RH: SCOPE: a web server for practical de novo motif discovery. Nucleic Acids Res 2007, 35:W259-W264.
• [87]Burnside J, Ouyang M, Anderson A, Bernberg E, Lu C, Meyers BC, Green PJ, Markis M, Isaacs G, Huang E, Morgan RW: Deep sequencing of chicken microRNAs. BMC Genomics 2008, 9:185. BioMed Central Full Text
• [88]Lambeth LS, Yao Y, Smith LP, Zhao Y, Nair V: MicroRNAs 221 and 222 target p27Kip1 in Marek's disease virus-transformed tumour cell line MSB-1. J Gen Virol 2009, 90:1164-1171.
• [89]Yao Y, Zhao Y, Smith LP, Lawrie CH, Saunders NJ, Watson M, Nair V: Differential expression of microRNAs in Marek's disease virus-transformed T-lymphoma cell lines. J Gen Virol 2009, 90:1551-1559.
• [90]Xu H, Yao Y, Smith LP, Nair V: MicroRNA-26a-mediated regulation of interleukin-2 expression in transformed avian lymphocyte lines. Cancer Cell Int 2010, 10:15. http://www.ncbi.nlm.nih.gov/pubmed/20441582?dopt=Citation webcite BioMed Central Full Text
• [91]Wang X: miRDB: a microRNA target prediction and functional annotation database with a wiki interface. RNA 2008, 14:1012-1017.
• [92]Wang X: El Naqa IM: Prediction of both conserved and nonconserved microRNA targets in animals. Bioinformatics 2008, 24:325-332.
• [93]Hoffmann A, Baltimore D: Circuitry of nuclear factor kappaB signaling. Immunol Rev 2006, 210:171-186.
• [94]Demchenko YN, Glebov OK, Zingone A, Keats JJ, Bergsagel PL, Kuehl WM: Classical and/or alternative NF{kappa}B pathway activation in multiple myeloma. Blood 2010, 115(17):3541-3552. Epub 2010 Jan 6. http://www.ncbi.nlm.nih.gov/pubmed/20053756?dopt=Citation webcite
• [95]Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J, et al.: Frequent inactivation of A20 in B-cell lymphomas. Nature 2009, 459:712-716.
• [96]Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M: The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 1997, 91:243-252.
• [97]Wu C, Ghosh S: Differential phosphorylation of the signal-responsive domain of I kappa B alpha and I kappa B beta by I kappa B kinases. J Biol Chem 2003, 278:31980-31987.
• [98]Lin R, Beauparlant P, Makris C, Meloche S, Hiscott J: Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. Mol Cell Biol 1996, 16:1401-1409.
• [99]McElhinny JA, Trushin SA, Bren GD, Chester N, Paya CV: Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, and T-291 and is required for its degradation. Mol Cell Biol 1996, 16:899-906.
• [100]Schwarz EM, Van Antwerp D, Verma IM: Constitutive phosphorylation of IkappaBalpha by casein kinase II occurs preferentially at serine 293: requirement for degradation of free IkappaBalpha. Mol Cell Biol 1996, 16:3554-3559.
• [101]Schumacher D, Tischer BK, Teifke JP, Wink K, Osterrieder N: Generation of a permanent cell line that supports efficient growth of Marek's disease virus (MDV) by constitutive expression of MDV glycoprotein E. J Gen Virol 2002, 83:1987-1992.
• [102]Stone HA: Use of highly inbred chickens in research. USDA Agricultural Research Service Technical Bulletin No - 1514; 1975:1-21.
• [103]Bacon LD, Hunt HD, Cheng HH: A review of the development of chicken lines to resolve genes determining resistance to diseases. Poult Sci 2000, 79:1082-1093.
• [104]Dennis R, Zhang HM, Cheng HW: Effect of selection for resistance and susceptibility to viral diseases on concentrations of dopamine and immunological parameters in six-week-old chickens. Poult Sci 2006, 85:2135-2140.
• [105]Tsunoda T, Takagi T: Estimating transcription factor bindability on DNA. Bioinformatics 1999, 15:622-630.
• [106]Mantovani A: Molecular pathways linking inflammation and cancer. Curr Mol Med 2010, 10:369-373. http://www.ncbi.nlm.nih.gov/pubmed/20455855?dopt=Citation webcite
• [107]Rayet B, Gelinas C: Aberrant rel/nfkb genes and activity in human cancer. Oncogene 1999, 18:6938-6947.
• [108]Lei X, Bai Z, Ye F, Xie J, Kim CG, Huang Y, Gao SJ: Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol 12:193-199. http://www.ncbi.nlm.nih.gov/pubmed/20081837?dopt=Citation webcite
• [109]Sadagopan S, Sharma-Walia N, Veettil MV, Raghu H, Sivakumar R, Bottero V, Chandran B: Kaposi's sarcoma-associated herpesvirus induces sustained NF-kappaB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression. J Virol 2007, 81:3949-3968.
• [110]Martin D, Galisteo R, Ji Y, Montaner S, Gutkind JS: An NF-kappaB gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia. Oncogene 2008, 27:1844-1852.
• [111]Keller SA, Hernandez-Hopkins D, Vider J, Ponomarev V, Hyjek E, Schattner EJ, Cesarman E: NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood 2006, 107:3295-3302.
• [112]Carbone A, Gloghini A, Dotti G: EBV-associated lymphoproliferative disorders: classification and treatment. Oncologist 2008, 13:577-585.
• [113]Ling L, Cao Z, Goeddel DV: NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Proc Natl Acad Sci USA 1998, 95:3792-3797.
• [114]Lawrence T, Bebien M, Liu GY, Nizet V, Karin M: IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 2005, 434:1138-1143.
• [115]Bonizzi G, Karin M: The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 2004, 25:280-288.
• [116]Sun SC, Cesarman E: NF-kappaB as a Target for Oncogenic Viruses. Curr Top Microbiol Immunol 2010, 349:197-244. http://www.ncbi.nlm.nih.gov/pubmed/20845110?dopt=Citation webcite
• [117]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 USA 2010, 107:18103-18108. http://www.ncbi.nlm.nih.gov/pubmed/20923877?dopt=Citation webcite
• [118]Murray RJ, Kurilla MG, Brooks JM, Thomas WA, Rowe M, Kieff E, Rickinson AB: Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies. J Exp Med 1992, 176:157-168.
• [119]Omar AR, Schat KA: Syngeneic Marek's disease virus (MDV)-specific cell-mediated immune responses against immediate early, late, and unique MDV proteins. Virology 1996, 222:87-99.
• [120]Khanna R, Burrows SR, Nicholls J, Poulsen LM: Identification of cytotoxic T cell epitopes within Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1): evidence for HLA A2 supertype-restricted immune recognition of EBV-infected cells by LMP1-specific cytotoxic T lymphocytes. Eur J Immunol 1998, 28:451-458.
• [121]Lupiani B, Lee LF, Cui X, Gimeno I, Anderson A, Morgan RW, Silva RF, Witter RL, Kung HJ, Reddy SM: Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication. Proc Natl Acad Sci USA 2004, 101:11815-11820.
• [122]Ajithdoss DK, Reddy SM, Suchodolski PF, Lee LF, Kung HJ, Lupiani B: In vitro characterization of the Meq proteins of Marek's disease virus vaccine strain CVI988. Virus Res 2009, 142:57-67.
• [123]Suchodolski PF, Izumiya Y, Lupiani B, Ajithdoss DK, Lee LF, Kung HJ, Reddy SM: Both homo and heterodimers of Marek's disease virus encoded Meq protein contribute to transformation of lymphocytes in chickens. Virology 2010, 399:312-321. http://www.ncbi.nlm.nih.gov/pubmed/20137800?dopt=Citation webcite
• [124]Deng X, Li X, Shen Y, Qiu Y, Shi Z, Shao D, Jin Y, Chen H, Ding C, Li L, et al.: The Meq oncoprotein of Marek's disease virus interacts with p53 and inhibits its transcriptional and apoptotic activities. Virol J 2010, 7:348. http://www.ncbi.nlm.nih.gov/pubmed/21110861?dopt=Citation webcite BioMed Central Full Text
• [125]Franchina M, Kadin ME, Abraham LJ: Polymorphism of the CD30 promoter microsatellite repressive element is associated with development of primary cutaneous lymphoproliferative disorders. Cancer Epidemiol Biomarkers Prev 2005, 14:1322-1325.
• [126]Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 2002, 99:4283-4297.
• [127]Matsuyama-Kato A, Murata S, Isezaki M, Kano R, Takasaki S, Ichii O, Konnai S, Ohashi K: Molecular characterization of immunoinhibitory factors PD-1/PD-L1 in chickens infected with Marek's disease virus. Virol J 2012, 9:94. BioMed Central Full Text
• [128]Rachinel N, Salles G: The host-tumor interface in B-cell non-Hodgkin lymphoma: a new world to investigate. Curr Hematol Malig Rep 2009, 4:196-201.
• [129]Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM: CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4 + CD25 T cells. Blood 2007, 110:2537-2544.
• [130]Mittal S, Marshall NA, Duncan L, Culligan DJ, Barker RN, Vickers MA: Local and systemic induction of CD4 + CD25+ regulatory T-cell population by non-Hodgkin lymphoma. Blood 2008, 111:5359-5370.
• [131]Maggio E, van den Berg A, Diepstra A, Kluiver J, Visser L, Poppema S: Chemokines, cytokines and their receptors in Hodgkin's lymphoma cell lines and tissues. Ann Oncol 2002, 13(Suppl 1):52-56.
• [132]Baumforth KR, Birgersdotter A, Reynolds GM, Wei W, Kapatai G, Flavell JR, Kalk E, Piper K, Lee S, Machado L, et al.: Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells. Am J Pathol 2008, 173:195-204.
• [133]Engel AT, Selvaraj RK, Kamil JP, Osterrieder N, Kaufer BB: Marek's disease viral interleukin-8 (vIL-8) promotes lymphoma formation through targeted recruitment of B-cells and CD4+CD25+ T-cells. J Virol 2012, 86(16):8536-8545. Epub 2012 May 30.( http://www.ncbi.nlm.nih.gov/pubmed/22647701 webcite
• [134]Griffiths-Jones S: The microRNA Registry. Nucleic Acids Res 2004, 32:D109-D111.
• [135]Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A: Enright AJ: miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006, 34:D140-D144.
• [136]McCarthy FM, Burgess SC, van den Berg BH, Koter MD, Pharr GT: Differential detergent fractionation for non-electrophoretic eukaryote cell proteomics. J Proteome Res 2005, 4:316-324.
• [137]Pendarvis K, Kumar R, Burgess SC, Nanduri B: An automated proteomic data analysis workflow for mass spectrometry. BMC Bioinformatics 2009, 10(Suppl 11):S17. BioMed Central Full Text
• [138]Beausoleil SA, Villen J, Gerber SA, Rush J, Gygi SP: A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol 2006, 24:1285-1292.
• [139]Han G, Ye M, Jiang X, Chen R, Ren J, Xue Y, Wang F, Song C, Yao X, Zou H: Comprehensive and reliable phosphorylation site mapping of individual phosphoproteins by combination of multiple stage mass spectrometric analysis with a target-decoy database search. Anal Chem 2009, 81:5794-5805.
• [140]Sif S, Gilmore TD: NF-kappa B p100 is one of the high-molecular-weight proteins complexed with the v-Rel oncoprotein in transformed chicken spleen cells. J Virol 1993, 67:7612-7617.
• [141]Capobianco AJ, Chang D, Mosialos G, Gilmore TD: p105, the NF-kappa B p50 precursor protein, is one of the cellular proteins complexed with the v-Rel oncoprotein in transformed chicken spleen cells. J Virol 1992, 66:3758-3767.
• [142]McCarthy FM, Bridges SM, Wang N, Magee GB, Williams WP, Luthe DS, Burgess SC: AgBase: a unified resource for functional analysis in agriculture. Nucleic Acids Res 2007, 35:D599-D603.