Marek's disease virus Meq transforms chicken cells via the v-Jun transcriptional cascade: A converging transforming pathway for avian oncoviruses

Levy, Alon M.; Gilad, Oren; Xia, Liang; Izumiya, Yoshihiro; Choi, Jonathan; Tsalenko, Anya; Yakhini, Zohar; Witter, R. L.; Lee, Lucy; Cardona, Carol J.; Kung, Hsing Jien

doi:10.1073/pnas.0506849102

Cited by 94 publications

(71 citation statements)

References 35 publications

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“…Colony formation in soft agar. Colony formation in soft agar is a marker of transformation, and Meq expression in fibroblasts has been shown to promote anchorage-independent growth (20). Soft-agar assay was used to test the ability of Meq homodimers to promote colony formation in soft agar.…”

Section: Resultsmentioning

confidence: 99%

“…However, the mechanisms of Meq transformation remain unknown. In vitro characterization of Meq DNA binding and transactivation or repression activities have provided support for the hypothesis that Meq homodimers and heterodimers have distinct roles in MDV-1 pathogenesis (13,20,21,29); however, the role of Meq homodimers and heterodimers in MDV-1 pathogenesis has not been characterized.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro data support the oncogenic nature of Meq, which can promote anchorage-independent growth, cell cycle progression, and antiapoptosis (23,24). Recently, in vitro expression of Meq was shown to upregulate genes similar to those upregulated by v-Jun, suggesting that Meq transforms via a v-Jun transforming pathway (20). In addition, knockdown of c-jun diminishes Meq's transforming ability in vitro, strongly suggesting that a Meq/Jun partnership plays a key role in Meq's oncogenic properties.…”

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confidence: 99%

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

Suchodolski

Izumiya

Lupiani

et al. 2009

J Virol

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Suchodolski

Izumiya

Lupiani

et al. 2009

J Virol

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“…The direct role of Meq in MDV oncogenicity has been clearly demonstrated by the abolition of oncogenicity in Meq-deleted mutant viruses (Lee et al, 2008;Lupiani et al, 2004). Although all of the molecular mechanisms of Meq-induced oncogenicity are yet to be identified, an increasing amount of data from various laboratories suggest that the DNA-binding and transcriptional functions of Meq are strongly modulated by its interaction with multiple protein partners ( Levy et al, 2005;Nair & Kung, 2004;Osterrieder et al, 2006). Structurally, the 339 aa Meq protein comprises an Nterminal bZIP domain, a proline-rich unstructured middle region and a C-terminal transactivation domain.…”

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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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“…The transactivation domain is characterized by two and a half proline-rich repeats (PRR), which display the transrepression effect (Liu and Kung, 2000). Meq contributes to oncogenicity by altering the expression of various cellular genes (Levy et al, 2005). Therefore, changes in the structure of the Meq protein, such as amino acid substitutions in the BR and PRR, may alter transactivation activity, indicating that diversity in Meq may alter its function and subsequently contribute to oncogenicity (unpublished data).…”

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Surveillance of Marek’s disease virus in migratory and sedentary birds in Hokkaido, Japan

Shiro

Hayashi

Kato

et al. 2012

The Veterinary Journal

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Marek's disease virus serotype 1 (MDV-1) strains cause malignant lymphoma in chickens.MDV-1 has been previously reported to be widespread in white-fronted geese (Anser albifrons); however, the prevalence of MDV-1 in other wild birds has not been determined.In this study, we investigated the prevalence of MDV-1 in various wild birds in Hokkaido, Japan. The MDV-1 genome was widespread in geese and ducks, but was not detected in other birds. MDV-1 was detected in both sedentary and migratory species. These results suggest that, in Japan, MDV-1 is widespread in wild goose and duck populations, and that resident ducks may be significant carriers and reservoirs of MDV-1.

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Marek's disease virus Meq transforms chicken cells via the v-Jun transcriptional cascade: A converging transforming pathway for avian oncoviruses

Abstract: Marek's disease virus (MDV) is

Cited by 94 publications

References 35 publications

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

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

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

Surveillance of Marek’s disease virus in migratory and sedentary birds in Hokkaido, Japan

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