Homodimerization of Marek's Disease Virus-Encoded Meq Protein Is Not Sufficient for Transformation of Lymphocytes in Chickens

Suchodolski, Paulette F.; Izumiya, Yoshihiro; Lupiani, Blanca; Ajithdoss, Dharani K.; Gilad, Oren; Lee, Lucy F.; Kung, Hsing Jien; Reddy, Sanjay M.

doi:10.1128/jvi.01630-08

Cited by 41 publications

(27 citation statements)

References 36 publications

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“…dimerization abolish viral oncogenicity (Brown et al, 2006), suggesting that partnering with other bZIP proteins is important for Meq oncogenicity. Recent data have also shown that homodimerization alone is insufficient for Meq-induced transformation by MDV (Suchodolski et al, 2009). The N-terminal region of Meq contains a PLDLS motif, also present in other viral oncoproteins such as adenovirus E1A (Chinnadurai, 2002(Chinnadurai, , 2009) and EBV EBNA3A (Hickabottom et al, 2002), with which they interact with the transcriptional co-repressor C-terminal binding protein-1 (CtBP).…”

Section: Introductionmentioning

confidence: 99%

Interaction of Marek's disease virus oncoprotein Meq with heat-shock protein 70 in lymphoid tumour cells

Zhao

Kurian

et al. 2009

Journal of General Virology

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Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that induces the rapid onset of T-cell lymphomas in poultry. The MDV-encoded oncoprotein Meq plays an important role in oncogenicity, as its deletion abolishes the ability of the virus to induce tumours. It has been shown previously that Meq oncogenicity is linked to its interaction with C-terminal binding protein 1 (CtBP), a property also shared by other virus-encoded oncoproteins such as adenovirus E1A and Epstein-Barr virus EBNA3A and -3C. Therefore, this study examined whether Meq also shares the properties of these viral oncoproteins in interacting with other binding partners such as heatshock protein 70 (Hsp70), a molecular chaperone protein linked to multiple cellular functions including neoplastic transformation. Confocal microscopic analysis demonstrated that MDV infection induced nuclear accumulation of Hsp70 and its co-localization with Meq. Biochemical evidence of Meq-Hsp70 interaction was obtained by two-way immunoprecipitation with Meqand Hsp70-specific antibodies. To demonstrate further the Meq-Hsp70 interaction in virusinduced lymphomas, recombinant MDV was generated expressing an N-terminal tandem affinity purification (TAP) tag-fused Meq by mutagenesis of the infectious BAC clone of the oncogenic MDV strain RB-1B. Demonstration of Hsp70 in the TAP-tag affinity purified Meq from tumours induced by the recombinant virus, using quadrupole time-of-flight tandem mass spectrometry analysis, further confirmed the Meq-Hsp70 interaction in the transformed lymphocytes. Given the well-documented evidence of the tumorigenic properties of Hsp70 and its interaction with a number of other known viral oncoproteins, demonstration of the interaction of Meq and Hsp70 is significant in MDV oncogenesis. INTRODUCTIONCurrent estimates suggest that viruses are involved in 15-20 % of human cancers worldwide (Javier & Butel, 2008). Oncogenic viruses, as efficient inducers of cancers, have helped significantly in understanding the molecular mechanisms of oncogenesis. Marek's disease (MD), a highly oncogenic viral disease induced by Marek's disease virus (MDV), is widely seen as a natural model for virusinduced lymphomas (Calnek, 1986;Osterrieder et al., 2006). MDV induces rapid-onset CD4 + T-cell lymphomas within a few weeks of infection, and MD lymphomas have many biological parallels with tumours associated with human herpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV, human herpesvirus 8). For example, it has recently been shown that MDV and KSHV both encode an oncogenic microRNA-155 orthologue (Gottwein et al., 2007;Zhao et al., 2009), whilst EBV strongly induces host microRNA-155 expression (Yin et al., 2008). However, the most important viral gene associated with MD oncogenicity is Meq (MDV EcoRI Q), encoded from the repeat region (IR L /TR L ) of the MDV genome (Jones et al., 1992;Nair & Kung, 2004). The direct role of Meq in MDV oncogenicity has been clearly demonstrated by the abolition of oncogenicity in Meq-de...

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Section: Introductionmentioning

confidence: 99%

Interaction of Marek's disease virus oncoprotein Meq with heat-shock protein 70 in lymphoid tumour cells

Zhao

Kurian

et al. 2009

Journal of General Virology

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“…The best candidate for an MDV protein involved in histone modification is Meq, since it is one of the few proteins expressed during latency, has a nuclear distribution, binds DNA, and regulates transcription (9,49,50). The ability to repress transcription as a homodimer probably relates to its ability to interact with the cellular corepressor CtBP (8), and this provides a potential link to the polycomb complexes responsible for H3K27me3 (46).…”

Section: Discussionmentioning

confidence: 99%

“…The only homodimer binding site that has been identified in the MDV genome is at OriLyt, but several MERE-1 (AP-1) sites are found in the latencyassociated region (27,34). Meq homo-and heterodimerization and Meq binding to the cellular corepressor CtBP are all required for its oncogenic activity (8,9,30,49,50).…”

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confidence: 99%

Epigenetic Regulation of the Latency-Associated Region of Marek's Disease Virus in Tumor-Derived T-Cell Lines and Primary Lymphoma

Brown

Nair

Allday

2012

J Virol

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Meq is the major Marek's disease virus (MDV)-encoded oncoprotein and is essential for T-cell lymphomagenesis. Meq and several noncoding RNAs, including three microRNA (MiR) clusters, are expressed from the repeats of the MDV genome during latent infection of T cells. To investigate the state of the chromatin in this and flanking regions, we carried out chromatin immunoprecipitation (ChIP) analysis of covalent histone modifications and associated bound proteins. T-cell lines and a lymphoma were compared. The chromatin around the promoters for Meq and the noncoding RNAs in both cell lines and the lymphoma were associated with H3K9 acetylation and H3K4 trimethylation, which are marks of transcriptionally active chromatin. These correlated with bound Meq-c-Jun heterodimers. The only binding site for Meq homodimers is located at the lytic origin of replication (OriLyt), next to the lytic gene pp38. This region lacked active marks and was associated with repressive histone modifications (H3K27 and H3K9 trimethylation). DNA CpG methylation was investigated using methylated DNA precipitation (MeDP). In cell lines, DNA methylation was abundant across the repeats but noticeably reduced or absent around the active promoters. In primary tumors, CpG methylation occurred less than 2 months after infection, focused within the ICP4 gene. These data suggest that nonrandom de novo DNA methylation occurs early in lymphomagenesis. In addition, the histone data indicate a role for Meq in the epigenetic regulation of the MDV genome repeats in transformed T cells and suggest that the OriLyt region and the Meq/MiR region might be separated by chromatin boundary elements, and preliminary data on CTCF binding are consistent with this.

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“…Both types of dimers are required for GaHV-2-induced T lymphomagenesis: the Meq/Meq homodimer as a transrepressor on MERE (MEq response element, ACACA) and the Meq/Jun heterodimer as a transactivator on the AP-1 RE (6,8,(50)(51)(52). The predicted MERE repressor site, which, unlike the MERE of the pp14/38 promoter (6), is located just downstream from the TSS (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that Meq can form either heterodimers with other bZIP proteins, such as c-Jun, that bind to AP-1-responsive elements (REs), such as CRE (TGACGTCA) or TRE (TGASTCA), or homodimers that bind to Meq-responsive element II (MEREII) (RA CACACAY) and with a lower affinity to MEREI (GAGTGATGA CGTCATC) (5,6). The transactivation properties of Meq depend on its dimerization partner: Meq/Meq homodimers repress expression of the pp24/38 gene by binding to a MEREII site (6), whereas Jun/Meq heterodimers transactivate the expression of ICP4 and meq by binding to AP-1 REs (6)(7)(8). Meq may also regulate cellular genes, such as those for interleukin-2 (IL-2) (6), CD30 (1), and Bcl-2 (7), and may increase the transcription of genes involved in growth and antiapoptotic pathways, such as the Jun pathways, during the induction of MD virus (MDV) lymphomagenesis (9).…”

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confidence: 99%

The Oncogenic MicroRNA OncomiR-21 Overexpressed during Marek's Disease Lymphomagenesis Is Transactivated by the Viral Oncoprotein Meq

Stik

Dambrine

Pfeffer

et al. 2013

J Virol

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cGallid herpesvirus 2 (GaHV-2) is an oncogenic herpesvirus that causes T lymphoma in chicken. GaHV-2 encodes a basic leucine zipper (bZIP) protein of the AP-1 family, Meq. Upon formation of homo-or heterodimers with c-Jun, Meq may modulate the expression of viral and cellular genes involved in lymphomagenesis. GaHV-2 also encodes viral microRNAs (miRNAs) involved in latency and apoptosis escape. However, little is known about cellular miRNA deregulation during the development of GaHV-2-associated lymphoma. We determined the cellular miRNA expression profiles of chickens infected with a very virulent strain (RB-1B) or a vaccine strain (CVI988) or noninfected. Among the most deregulated cellular miRNAs, we focused our efforts on gga-miR-21, which is upregulated during GaHV-2 infection. We mapped the gga-miR-21 promoter to the 10th intron of the TMEM49 gene and found it to be driven by AP-1-and Ets-responsive elements. We show here that the viral oncoprotein Meq binds to this promoter, thereby transactivating gga-miR-21 expression. We confirmed that this miRNA targets chicken programmed death cell 4 (PDCD4) and promotes tumor cell growth and apoptosis escape. Finally, gga-miR-21 was overexpressed only during infection with a very virulent strain (RB-1B) and not during infection with a nononcogenic strain (CVI988), providing further evidence for its role in GaHV-2 lymphomagenesis. Our data therefore suggest an additional role for Meq in GaHV-2-mediated lymphomagenesis through the induction of miR-21 expression.

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Homodimerization of Marek's Disease Virus-Encoded Meq Protein Is Not Sufficient for Transformation of Lymphocytes in Chickens

Abstract: Marek's disease virus (MDV),

Cited by 41 publications

References 36 publications

Interaction of Marek's disease virus oncoprotein Meq with heat-shock protein 70 in lymphoid tumour cells

Interaction of Marek's disease virus oncoprotein Meq with heat-shock protein 70 in lymphoid tumour cells

Epigenetic Regulation of the Latency-Associated Region of Marek's Disease Virus in Tumor-Derived T-Cell Lines and Primary Lymphoma

The Oncogenic MicroRNA OncomiR-21 Overexpressed during Marek's Disease Lymphomagenesis Is Transactivated by the Viral Oncoprotein Meq

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