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

Kumar S, Kunec D, Buza JJ, Chiang HI, Zhou H, Subramaniam S, Pendarvis K, Cheng HH, Burgess SC - BMC Syst Biol (2012)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathobiology and Population Medicine, Mississippi State University, MS 39762, USA. skumar@cvm.msstate.edu

ABSTRACT

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.

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Schematic diagram of the hypothesized Meq-CD30- NF-κB feed forward loop, subcellular localization and phosphorylation status of different isoforms of NF-κB. Schematic diagram of hypothesized Meq-CD30-NF-κB feed forward loop and showing differential expression of NF-κB isoforms (A). Comparison of the amount and sub cellular localization of NF-κB isoforms: circle size proportionately portrays relative protein amount; equal size indicates no differential expression at P < 0.05 (B). In CD30hi lymphocytes most IKKα is phosphorylated at the canonical residues that regulate proteasome-mediated degradation and destabilization, whereas in CD30lo lymphocytes most IKKα and IKKβ is unphosphorylated at these same residues (C).
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Figure 4: Schematic diagram of the hypothesized Meq-CD30- NF-κB feed forward loop, subcellular localization and phosphorylation status of different isoforms of NF-κB. Schematic diagram of hypothesized Meq-CD30-NF-κB feed forward loop and showing differential expression of NF-κB isoforms (A). Comparison of the amount and sub cellular localization of NF-κB isoforms: circle size proportionately portrays relative protein amount; equal size indicates no differential expression at P < 0.05 (B). In CD30hi lymphocytes most IKKα is phosphorylated at the canonical residues that regulate proteasome-mediated degradation and destabilization, whereas in CD30lo lymphocytes most IKKα and IKKβ is unphosphorylated at these same residues (C).

Mentions: We found that NF-κB p50 (functional NF-κB1), p65 (RelA) and RelB and IKKα proteins all increased in CD30hi lymphocytes (Figure4A) and most p50 and all p65 protein (which form the most common and abundant classical dimers) were nuclear (Figure4B, Additional file1). NF-κB signaling is controlled by negative feedback via IκBα and A20/TNIP2 (tumor necrosis factor alpha-induced protein 3 [TNFAIP3] in chicken) transcriptional induction[95] and we found TNFAIP3 mRNA and protein unchanged but IκBα mRNA decreased, suggesting that this negative feedback mechanism is suppressed. The TNFAIP3 and IκBα promoters have 18 (all MERE II) and 9 (3 MERE I and 6 MERE II) predicted Meq-binding sites, respectively, which suggest that MDV has evolved to maintain NF-κB activation. Not only do CD30hi lymphocytes have more of all NF-κB isoforms but more are nuclear (Figure4B, Additional file1), again suggesting NF-κB activation. Furthermore in CD30hi lymphocytes, most IKKα is phosphorylated at the canonical residues that regulate proteasome-mediated degradation[96,97] and destabilization[98-100], whereas the opposite occurred for IKKα in CD30lo lymphocytes (Figure4C, Additional file1).


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

Kumar S, Kunec D, Buza JJ, Chiang HI, Zhou H, Subramaniam S, Pendarvis K, Cheng HH, Burgess SC - BMC Syst Biol (2012)

Schematic diagram of the hypothesized Meq-CD30- NF-κB feed forward loop, subcellular localization and phosphorylation status of different isoforms of NF-κB. Schematic diagram of hypothesized Meq-CD30-NF-κB feed forward loop and showing differential expression of NF-κB isoforms (A). Comparison of the amount and sub cellular localization of NF-κB isoforms: circle size proportionately portrays relative protein amount; equal size indicates no differential expression at P < 0.05 (B). In CD30hi lymphocytes most IKKα is phosphorylated at the canonical residues that regulate proteasome-mediated degradation and destabilization, whereas in CD30lo lymphocytes most IKKα and IKKβ is unphosphorylated at these same residues (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472249&req=5

Figure 4: Schematic diagram of the hypothesized Meq-CD30- NF-κB feed forward loop, subcellular localization and phosphorylation status of different isoforms of NF-κB. Schematic diagram of hypothesized Meq-CD30-NF-κB feed forward loop and showing differential expression of NF-κB isoforms (A). Comparison of the amount and sub cellular localization of NF-κB isoforms: circle size proportionately portrays relative protein amount; equal size indicates no differential expression at P < 0.05 (B). In CD30hi lymphocytes most IKKα is phosphorylated at the canonical residues that regulate proteasome-mediated degradation and destabilization, whereas in CD30lo lymphocytes most IKKα and IKKβ is unphosphorylated at these same residues (C).
Mentions: We found that NF-κB p50 (functional NF-κB1), p65 (RelA) and RelB and IKKα proteins all increased in CD30hi lymphocytes (Figure4A) and most p50 and all p65 protein (which form the most common and abundant classical dimers) were nuclear (Figure4B, Additional file1). NF-κB signaling is controlled by negative feedback via IκBα and A20/TNIP2 (tumor necrosis factor alpha-induced protein 3 [TNFAIP3] in chicken) transcriptional induction[95] and we found TNFAIP3 mRNA and protein unchanged but IκBα mRNA decreased, suggesting that this negative feedback mechanism is suppressed. The TNFAIP3 and IκBα promoters have 18 (all MERE II) and 9 (3 MERE I and 6 MERE II) predicted Meq-binding sites, respectively, which suggest that MDV has evolved to maintain NF-κB activation. Not only do CD30hi lymphocytes have more of all NF-κB isoforms but more are nuclear (Figure4B, Additional file1), again suggesting NF-κB activation. Furthermore in CD30hi lymphocytes, most IKKα is phosphorylated at the canonical residues that regulate proteasome-mediated degradation[96,97] and destabilization[98-100], whereas the opposite occurred for IKKα in CD30lo lymphocytes (Figure4C, Additional file1).

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathobiology and Population Medicine, Mississippi State University, MS 39762, USA. skumar@cvm.msstate.edu

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus