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354 | Lupiani et al.

vitro (Isfort et al., 1992). Later study demonstrated that vLIP is EBNA (EBV nuclear antigen) 1, 2 and 3C are all DNA binding
a secreted glycoprotein lacking detectable lipase activity in vitro, proteins and transcription factors. EBNA1 is primarily involved
and mutagenesis experiment concluded that vLIP is not required in maintenance and replication of the viral episome. EBNA2
for virus replication but is a MDV virulence factor which plays a and 3C are important for transformation of B-lymphocytes and
role in MDV pathogenesis (Kamil et al., 2005). regulation of latent gene expression (Young and Murray, 2003).
In addition, some genes located at ends of UL region, includ- EBNA2 is a general transcriptional activator, and EBNA3C
ing MDV009, MDV011, MDV012, MDV069, and MDV072 is a transcriptional repressor. There are significant similarities
genes, have no homology to non-avian herpesviruses suggesting between Meq and EBNA3C. Both cooperate with the cellular
that they might be important for avian host range (Tulman et al., Ras oncogene to transform rodent fibroblasts in culture (Parker
2000). et al., 1996) and to accelerate cell cycle progression (Parker et al.,
2000). Both bind CtBP, a strong cellular transcriptional repressor
(Touitou et al., 2001). In addition, EBNA3C targets the cellular
Molecular oncogenesis Rb protein for degradation through recruitment of the S-phase
MDV is the most potent oncogenic herpesvirus, causing T-cell kinase-associated protein 1 (SKP1)/Cullin/F-box (SCF) com-
lymphoma within 2–3 weeks of infection in nearly 100% of plex ubiquitin ligase (Knight et al., 2005). KSHV, the causative
infected chickens. Accordingly, it is among the most economically agent for both Kaposi’s sarcoma and pleural effusion lymphoma,
important of all infectious diseases affecting poultry production encodes several latent proteins, of which latent associated nuclear
worldwide. A single viral oncogene, meq, whose function is antigen (LANA) is the most relevant to our discussion. LANA
absolutely required for tumorigenesis, has been identified. Impor- is involved in both maintenance of the viral episome and in cell
tantly the oncogenic feature of Meq is separable from its function transformation. Although the structure of LANA and Meq are
in viral replication, making MDV infection a unique model to distinct, there are several striking functional similarities. Both
study cancer virology. In addition, a genetic system to manipulate Meq and LANA (i) associate with the c-Jun transcription factor
viral genes as well as an infection model to evaluate oncogenicity as co-activators and activate the AP-1 promoter (An et al., 2004),
of the virus are well established. These features provide a unique (ii) interact with p53 and Rb tumour suppressor proteins to
opportunity to systematically explore the molecular mechanisms deregulate the cell cycle (Friborg et al., 1999; Radkov et al., 2000;
of viral oncogenesis in natural host. In this section, we describe An et al., 2005), and (iii) cooperate with the Ras oncoprotein to
the possible molecular mechanisms of MDV oncogenicity. transform rat fibroblasts (Radkov et al., 2000) and protect cells
from apoptosis (Friborg et al., 1999; Sato et al., 2001). LANA
Tumour suppressors and viral oncogenesis interacts with RING3 and c-Jun to regionally open up chromatin
Like in other DNA tumour viruses, several MDV genes which to transcribe latent viral genes and certain cellular genes including
contribute to oncogenesis have been identified, with Meq as the telomerase gene (An et al., 2004; Verma et al., 2004; Viejo-
being the most critical one. Although DNA tumour virus onco- Borbolla et al., 2005). MDV Meq also heterodimerizes with
genes share little sequence homology, one common property is c-Jun to generate open chromatin structures (Levy-Barda et al.,
their ability to inactivate cellular tumour suppressors, thereby 2011; Ramadan and Meerang, 2011; Mallette et al., 2012). The
deregulating the cell cycle and facilitating viral replication. The functional duality of herpesvirus latent proteins (e.g. Meq and
tumour suppressor commonly inactivated by viral oncogenes is LANA), as transcriptional factors and regulators of tumour sup-
p53, which is often activated during DNA tumour virus infec- pressors, is the underlying basis for the molecular mechanisms of
tion, due to the generation of DNA lesion-like free ends during these proteins in cell transformation and viral latency.
viral replication. As a result, DNA tumour virus oncogenes have
evolved ways to inactivate p53. For small DNA tumour viruses, Transcriptional activation: the Jun oncogenic
the viral oncogenes directly associate with p53. For example, ade- pathway
novirus E1B, SV40 large-T antigen, interact with and sequester Heterodimers Jun/Fos and their related family members (JunB,
p53. Degradation of p53 prevents host cells from apoptosis and/ JunD, Fra1 etc.), collectively called AP-1, are generally strong
or cell cycle arrest, enabling the completion of virus replication. transactivators and effectors of the Ras pathway. There is over-
MDV encoded Meq protein also interacts with p53 and deregu- whelming evidence that AP-1 plays a major role in the oncogenic
late its transcription function (Deng et al., 2010), and leads to p53 pathway of a variety of malignancies including leukaemia and
degradation. lymphoma. Both Jun and Fos were originally discovered as ret-
roviral oncogenes and heightened AP-1 expression and activities
Common features between human herpesvirus were detected in leukaemias (Mao et al., 2003) including those
latent proteins and MDV Meq caused by HTLV-1 (Iwai et al., 2001; Arnulf et al., 2002). The
There are similarities among the latent proteins of other onco- target genes for Jun/Fos are molecules including cytokines,
genic herpesviruses (EBV, KSHV) and MDV. EBV and KSHV are chemokines and metalloproteinases that deregulate the cell cycle
human oncogenic herpesviruses, which express transcription fac- and promote invasiveness. For T-cell transformation in particular,
tors, sometimes multiple, which play diverse roles in viral episome c-Jun activation induces the release of transforming growth factor
maintenance, latent DNA replication, transcriptional regulation, β (TGF-β), which suppresses the immune surveillance function
and cellular transformation during latent infection. In EBV, of other T-cells, and at the same time, interacts with SMAD3 to