Nuclear receptors and their role in epstein — barr virus induced b cell transformation
Epstein — Barr virus (EBV) is a lymphotropic virus that infects more than 90% of the human population, and targets B cells for
 infection. Infection of human B cells leads to the malignant transformation and eventual immortalization. In latency III infection
 six EBV-encoded nuclear...
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| Date: | 2009 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2009
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| Cite this: | Nuclear receptors and their role in epstein — barr virus induced b cell transformation / S.P. Yenamandra, G. Klein, E. Kashuba // Experimental Oncology. — 2009. — Т. 31, № 2. — С. 67-73. — Бібліогр.: 81 назв. — англ. |
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| author | Yenamandra, S.P. Klein, G. Kashuba, E. |
| author_facet | Yenamandra, S.P. Klein, G. Kashuba, E. |
| citation_txt | Nuclear receptors and their role in epstein — barr virus induced b cell transformation / S.P. Yenamandra, G. Klein, E. Kashuba // Experimental Oncology. — 2009. — Т. 31, № 2. — С. 67-73. — Бібліогр.: 81 назв. — англ. |
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| description | Epstein — Barr virus (EBV) is a lymphotropic virus that infects more than 90% of the human population, and targets B cells for
infection. Infection of human B cells leads to the malignant transformation and eventual immortalization. In latency III infection
six EBV-encoded nuclear antigens (EBNAs) and three latent membrane proteins (LMPs) are expressed in the transformed cells
that can grow as a lymphoblastoid cell lines in vitro. These proteins hijack the normal B cell growth pathways by activating the
constitutive growth promotion and external survival signals. We have determined a set of the nuclear receptors that are up- (and
down-) regulated in the latency III infected cells at the mRNA level. In the present paper we discussed the possible role of these
receptors in B cell transformation upon EBV infection based on the literature data.
|
| first_indexed | 2025-12-07T18:45:18Z |
| format | Article |
| fulltext |
Experimental Oncology 31, 67–73, 2009 (June) 67
MAJOR FEATURES OF HERPESVIRUSES
Herpesviruses are often associated with different
human diseases. One of the common features of all the
members of the human herpesvirus (HHV) family is their
ability to establish life-long persistence in the host after
the primary infection. The latent infection by the human
gamma (γ) herpesviruses, Epstein — Barr virus (EBV) and
Kaposi’s sarcoma virus (HHV8), could be established in
lymphoid tissues. EBV, which was first identified in 1964,
is a lymphotropic virus that infects more than 90% of the
human population, and targets B cells for infection.
The primary infection may be asymptomatic and
often occurs in early childhood. When the infection
occurs later on in life, EBV causes infectious mono-
nucleosis (IM). In immunosuppressed hosts, such
as transplant recipients and AIDS patients, EBV may
cause post-transplant lymphoproliferative disease
(PTLD). EBV is also associated with several malignan-
cies, such as Burkitt’s lymphoma (BL), nasopharyngeal
carcinoma (NPC), and Hodgkin’s lymphoma (HL).
It is considered that the virus enters the host by
infecting B cells, which infiltrate the epithelium of the
oropharynx. After infection, the viral latent proteins
are produced and the B cells turn into large immuno-
blasts that express six EBV-encoded nuclear antigens
(EBNAs), three latent membrane proteins (LMPs) and
two small non-polyadenylated RNAs (EBERs). Such
cells may be targeted by cytotoxic T lymphocytes (CTLs)
reacting with the latency associated viral antigens.
The activated cells differentiate into antibody
producing cells, and migrate to the oropharyngeal
mucosa. In some of them lytic gene expression is
activated and new virus particles are produced. The
virus is usually shed through the saliva of the infected
host. The EBV-infected memory B cell pool may be
enriched by re-entry of the latently infected cells into
the germinal centers, where clonal expansion takes
place (reviewed in [1, 2]).
INFECTION OF B CELLS WITH EBV IN VITRO
Infection of human B cells in vitro induces meta-
bolic activation, morphological transformation, cell
proliferation and eventual immortalization.
In EBV immortalized immunoblastic lines of non-
neoplastic origin (lymphoblastoid cell lines; LCLs) nine
viral proteins are expressed. Similar patterns of EBNAs
and LMPs expression take place in tonsil and blood B
cells of IM patients and in the lymphoblasts of individuals
with PTLD [3–5]. EBV is the most efficient transforming
tumor virus in vitro (reviewed in [6]). Six of the eleven
EBV-encoded gene products (EBNA-1, -2, -3, -5, -6,
LMP-1) are essential for EBV-mediated transforma-
tion [7]. The latency III genes hijack the normal B cell
growth pathways by activating of the constitutive growth
promotion and external survival signals.
EBV encodes EBNA-2 that activates and regulates
the transcription of Notch and PU.1 responsive promo-
ters of the cellular genes, such as c-myc, c-fgr, CD21
and CD23 promoters. EBNA-2 binding to RBP-Jκ results
in the constitutive expression of c-myc in LCLs ([8], for
review see [9]), leading to change in cell phenotype,
adhesion and activation molecules expression. LMP1
activates TNFα/CD40 downstream signaling pathways
that can stimulate cell growth and survival through acti-
vation of NFκB, jun and p38 MAPK (reviewed in [1]).
An aim of the present paper was to discuss the
putative functions of the nuclear receptors that were
NUCLEAR RECEPTORS AND THEIR ROLE IN EPSTEIN — BARR
VIRUS INDUCED B CELL TRANSFORMATION
S.P. Yenamandra1, 2, G. Klein1, E. Kashuba1, 2, 3, *
1Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm S17177, Sweden
2Center for Integrative Recognition in the Immune System (IRIS), Karolinska Institute, Stockholm
S17177, Sweden
3R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, Kyiv
03022, Ukraine
Epstein — Barr virus (EBV) is a lymphotropic virus that infects more than 90% of the human population, and targets B cells for
infection. Infection of human B cells leads to the malignant transformation and eventual immortalization. In latency III infection
six EBV-encoded nuclear antigens (EBNAs) and three latent membrane proteins (LMPs) are expressed in the transformed cells
that can grow as a lymphoblastoid cell lines in vitro. These proteins hijack the normal B cell growth pathways by activating the
constitutive growth promotion and external survival signals. We have determined a set of the nuclear receptors that are up- (and
down-) regulated in the latency III infected cells at the mRNA level. In the present paper we discussed the possible role of these
receptors in B cell transformation upon EBV infection based on the literature data.
Key Words: cell transformation, EBV, EBNA, expression profiling, microarray, nuclear receptor.
Received: April 4, 2009.
*Correspondence: Fax: 468330498
E-mail: Elena.Kashuba@ki.se
Abbreviations used: BL — Burkitt lymphoma; CTL — cytotoxic T
lymphocytes; EBER — EBV encoded small RNA; EBV — Epstein —
Barr virus; EBNA — EBV-encoded nuclear antigen; HHV — human
herpesvirus; HL — Hodgkin’s lymphoma; LCL — lymphoblastoid cell
line; LMP – latent membrane protein; NPC — nasopharyngeal car-
cinoma; PTLD — post-transplantation lymphoproliferative disease.
Exp Oncol 2009
31, 2, 67–73
REVIEWS
68 Experimental Oncology 31, 67–73, 2009 (June)
found to be differently expressed in the naïve and
EBV-transformed B lymphocytes (see current issue,
Yenamandra et al. [10]).
NUCLEAR RECEPTOR PROFILING
As it was demonstrated in [10], only 17 genes
showed consistent differences in expression — de-
crease in B cells, upregulation in EBV-infected cells
and LCLs, or vice versa. The expression of 5 genes was
elevated in EBV-transformed cells; whereas 12 genes
were downregulated in LCLs [10].
Nuclear receptors that were up-regulated
in the EBV-transformed cells
Nr2F2. Nuclear receptor subfamily 2, group F,
member 2. This receptor is also known as a tran-
scriptional factor COUP2, or COUPTFII (NP_066285,
OMIM *107773, gene is located on chromosome
15q26.1-26.2, protein consists of 414 amino acids).
The literature data concerning this receptor is quite
poor. However, it may play an important role in EBV
induced transformation, because COUPTFII is involved
in the repression of Notch signaling. It can also down-
regulate the Apolipoprotein 1 [11, 12] (Fig. 1, a).
Nr4A3. Nuclear receptor subfamily 4, group A,
member 3. This protein is also called the Mitogen-
induced orphan receptor, MINOR (NP_775290,
OMIM +600542, gene is located on chromosome
9q22, protein is 626 amino acids long). It belongs to
NUR77 fami ly proteins. It was shown that LPS, cy-
tokines, oxidized lipids, and low-density lipoproteins
induced Nr4A1-3 in macrophages (reviewed in [13]).
Overexpression of this protein may lead to the apop-
tosis of T cells. At certain conditions, MINOR supports
the survival of cells (reviewed in [14, 15]) (Fig. 1, b).
Nr4A3 can play an important role in the inflammatory
signaling, because Nr4A receptors 1–3 are induced by
inflammation (by NF-κB, for example) (see Fig. 1, b).
Nr6A1. Nuclear receptor subfamily 6, group
A, member 6. This receptor has few alternative
names — Germ cell nuclear factor (GCNF), and
Retinoid receptor-related testis associated receptor
(RTR) (NP_201591, OMIM *602778, gene is locali-
zed to chromosome 9q33-34.1, protein consists
of 480 amino acids). It is quite well studied protein
(reviewed in [16]). Recently, it was shown that loss of
Nr6A1 expression led to induction of Nanog, Oct4,
Sox2, Stella and FGF4 expression upon retinoic acid
(RA) treatment [17]. The other genes, such as Fgf8,
Wnt1, Pax2/5, En1/2, and Gbx2, were downregulated
in case of Nr6A1 expression loss [18]. An intriguing
feature of this orphan receptor is ability to recruit DNA
a
b
c
d
e
Fig. 1. a — Properties of cluster of Nr2F proteins. Nr2F2 down regulates Apoliprotein 1 and Notch signaling. The up-regulated recep-
tors are shown is the red font; the down-regulated receptors are shown in blue. Sign “T” indicates inhibition of a process or a protein;
stars — binding between proteins; text in green is related to EBV-field. b — Properties of cluster of NUR77 family proteins. NUR77 binds
to RelA, bcl-2 and can induce apoptosis. EBNA-2 binds to NUR77 and blocks apoptosis. c — Properties of Nr641, PPARG and RARA
nuclear receptors. Nr6A1 might be involved in the regulation of Notch signaling; PPARG can block NBκB pathway; RARA binds to Z
promoter of EBV and can prevent the lytic cycle. d — Properties of RXR proteins. These proteins bind to Z promoter of EBV and prevent
the induction of the lytic cycle. The up-regulated receptors are shown is the red font; the down-regulated receptors are shown in blue.
e — Properties of estrogen receptors: the cross talk between ER pathway and Aryl hydrocarbon (dioxin) receptor (AhR) pathway
Experimental Oncology 31, 67–73, 2009 (June) 69
methyltransferase (Dnmt3) to the Oct3/4 promoter,
which resulted in silencing by hypermethylation [19]
(Fig. 1, c).
RARA. Retinoic acid receptor α (NP_000955,
OMIM *180240, gene is located on chromosome
17q21.1, protein consists of 462 amino acids) is very
well studied receptor (reviewed in [20]). It binds to
DNA as a homodimer with the Retinoid X receptors
(RXRs). It was shown that activated RARA can block
growth of LCLs due to G0/G1 arrest, while activity of
CDK2, -4, and -6 was inhibited, as well as cyclin A,
D2 and D3 [21].
On the other hand, it was reported that EBV lytic
cycle activation was inhibited upon RA treatment due
to the direct binding between RARA and the EBV-en-
coded lytic protein BZLF1 [22, 23].
Earlier it was also found that retinoids inhibited
naïve B cell proliferation, but promoted cell survival
[24]. It is worth to mention that the promoter region of
RARA contains estrogen receptor response element
(see Fig. 1, c) [25].
RXRA. Retinoid X receptor α (NP_002948, OMIM
*180245, gene is located on chromosome 9q34.3,
protein consists of 462 amino acids). A ligand-bound
receptor can activate transcription as a homodimer or
heterodimer (with RARs, LXR, FXR, PPARG) from re-
sponsive elements containing two degenerate copies
of the consensus motif AGGTCA. The same sites are
used by RARs, THRs, VDR and RXRs (Fig. 1, d).
It was shown (as for RARA), that RXRA could bind
to the BZLF1 (Z-protein) and inhibit EBV lytic cycle
[26, 27].
It was reported that RXR agonist treatment led to
an activation of Bcl2a1 (BFL1) and, thus, decreased
apoptosis in the naïve T-cells [26]. Moreover, recently
it was found that EBNA-2 transactivated BFL1 through
RBP-Jκ [27]. BFL1 was activated by CD40, TNF, IL-1,
and NFκB as well.
Nuclear receptors that were down-regulated
in the EBV-transformed cells
PPAR-γ. Peroxisome proliferator-activated re-
ceptor γ, also known as PPARG (NP_619725, OMIM
*601487, gene is located on chromosome 3p21, protein
consists of 475 amino acids) forms dimer with RXRs to
activate transcription. It was shown that PPARG might
function as a promoter-specific repressor of NF-κB
target genes that regulate immunity and homeostasis
[28]. PPARG binds to Rel A [29]. Decrease in PPAR-γ
abolishes the nuclear export of RelA.
It was already shown that lymphocytes expressed
functioning PPARG, and its activation led to apoptosis,
or growth arrest [30, 31], or differentiation [32]. Inte-
restingly, the activation of PPARG in B cells by CD40
ligand protects spleen B cells and B cell lymphomas
tumor cells from apoptosis [33].
Another attractive feature of PPARG is the ability to
bind pRb and histone deacetylase 3 (HDAC3) [34]. By
binding to HDAC3, PPARG can induce cell cycle arrest
of pRb positive cells in G1 phase.
PPARG, as we mentioned above, can have both
transactivating and transrepressing activity [35].
PPARG can repress some IFN-γ and LPS-inducible
genes, such as IL-12 and IP10 (see Fig. 1, c). In their
turn, cytokines can repress the activity of PPARG by
inhibiting DNA binding [36].
ER-α. Estrogen receptor α, ESR (NP_000116,
OMIM *133430, gene is located on chromosome
6q25.1, 595 amino acids in the protein sequence).
It was shown that promoter methylation decreased
the level of ESR expression in colorectal tumors [37].
Recently, it was demonstrated that Arnt/AhR heterodi-
mer could bind to ESR1 (both, α and β). This multi-
protein complex (in the presence of p300) activates
transcription from ER responsive elements (ERRE)
[38] (Fig. 1, e).
It was shown that ER-α and -β are expressed in
peripheral blood B cells. B cells express more ER-β
than ER-α [39]. However, only ER-α is needed to up-
regulate immunoglobulin production. Both activated
forms are required for complete downregulation of
lymphopoiesis in the bone marrow of mice [40, 41].
ER-β receptor is known also as ER2, ESR2
(Q92731, OMIM *601663, gene is localized to chro-
mosome 14q, protein consists of 447 amino acids).
ER-β putative DNA-binding domain shows 96% identity
to that of ER-α, but the ligand-binding domain has
much lower homology — only 56%. Actually, binding
of ER-α to DNA and transcription of the ER-α depen-
dent genes are studied very well, but ER-β function
is poorly known. It was published recently that ER-β
was associated with mitochondria [42]. Interestingly,
that treatment of mice by ER-α selective agonist led to
the decrease in number of mature B cells, and to the
enhancement of INF-γ production and IL-6 suppres-
sion [43]. The most intriguing fact is that a disruption
of ER-β in mice led to myeloproliferative disease that
resembled chronic myeloid leukemia with lymphoid
blast crisis [44] (see Fig. 1, e).
Nr1H3. Nuclear receptor subfamily 1, group H,
member 3, also known as Liver X receptor α (LXRA)
(NP_005684, OMIM *602423, gene is localized to
chromosome 11p12, protein consists of 447 amino
acids). This protein binds to RXRs and to DNA as hete-
romider [45]. LXRs play important role in the lipid me-
tabolism and transport. It was shown that LXR ligands
could inhibit expression of the inflammatory regulators,
such, as INOS, COX-2, and IL6 in response to bacterial
infection or LPS stimulation [46]. Moreover, LXRs-null
mice are highly susceptible to infection with Listeria
monocytogenes [47] (see Fig. 1, c).
Nr2F1. Nuclear receptor subfamily 2, group F,
member 1, also known as transcription factor COUP1
(TFCOUP1) (NP_005645, OMIM *132890, gene is
located on chromosome 5q14, protein consists of 423
amino acids). It was shown that Nr2F1 recognizes DNA
consensus sites that are also sites for RARA, RXRs,
VDR, and THR. The receptor shows high homology to
v-ErbA protein. Interestingly that compared with naïve
B-cells, BLs, and LCLs, transcription factor Nr2F1
70 Experimental Oncology 31, 67–73, 2009 (June)
was up-regulated in Reed/Sternberg cells of HL [48].
Unfortunately, there are only few studies devoted to
Nr2F1 (see Fig. 1, a).
Nr3C1. Nuclear receptor subfamily 3, group C,
member 1. This receptor is known as glucocorticoid
receptor (GCCR) (NP_001018087, OMIM +138040,
gene is localized to chromosome 5q31, protein con-
sists of 777 amino acids). About two decades ago
it was shown that GCCR might enhance the B cell
maturation and immunoglobulin production [49, 50].
An attempt to measure the concentration and activity of
receptor in peripheral blood B cells and EBV-infected
B cells was carried out [51]. However, no difference
in the GCCR activity was observed. It was shown later
on, that LPS-treated B cells are more resistant to the
apoptosis, mediated by activated GCCR [52].
Interestingly, the activated GCCR induced CD40
mRNA [53] and could inhibit growth arrest due to RA
treatment [54]. The promoter of GCCR is down regu-
lated by PU.1 [55].
It was shown recently that endogenous glucocor-
ticoids are required for transcriptional suppression of
INF-γ [56]. At the same time, activated GCCR acts as
a co-activator for STAT5-dependent transcription [57]
(see Fig. 1, c).
Nr4A1. Nuclear receptor subfamily 4, group A,
member 1, homologues of mouse NUR77 (NP_775180,
OMIM *139139, gene is localized to chromosome
12q13, protein consists of 598 amino acids). It was
shown that this receptor was induced rapidly and
transiently by growth-stimulating agents in human
lymphocytes [58]. LPS treatment of macrophages
led to N4A1 induction by NF-κB [59]. In contrast to
transcriptionally active nuclear localization [60], Nr4A1
receptor exhibits its mitogenic effect through the target
gene regulation. Its pro-apoptotic effect is realized in
cytoplasm through regulation of mitochondrial activi-
ty [61]. It was found later that the orphan receptor is
bound to Bcl-2 and could convert it to killer [62].
It should be mentioned that at different conditions
and cell background NUR77 could be both induced
and repressed by TNF-α and NF-κB [60, 63, 64].
NUR77 was implicated in B cell apoptosis [65], and
EBNA-2 (but not LMP1) could protect B cells from
NUR77-induced apoptosis [66, 67] (see Fig. 1, b).
RORC. RAR-related orphan receptor γ (RORG)
(NP_005051, OMIM *602943, gene is located on
chromosome 1q21, protein contains 518 amino acids).
Importance of RORC was shown in experiments on
the homozygous null mice — they lacked peripheral
and mesenteric lymphnodes and Peyer patches [68,
69]. Another interesting feature of such mice is loss of
thymic expression of the anti-apoptotic factor Bcl-xL
[68, 70] (see Fig. 1, c).
RXRB. Retinoid X receptor β (NP_068811, OMIM
*180246, gene is localized to chromosome 6p21.3,
protein consists of 533 amino acids). This receptor acts
as transcription activator in the heterodimer with RARs,
VDR, THR, LXR, and Farnesoid X receptor (FXR).
RXRB increases their DNA binding and transacti-
vating ability of RARs, VDR, and THR [71, 72]. RXRB
promoter is down-regulated by TNF-α and this repres-
sion is mediated by p38 MAP kinase, independently
from NF-κB [73]. RXRB binds to Z protein as RXRA
does [22, 23] and this binding inhibits the EBV lytic
cycle (see Fig. 1, d).
THRB. Thyroid hormone receptor β (NP_000452,
OMIM +190160, gene is located on chromosome 3p24.3,
protein consists of 461 amino acids). This receptor was
known before as ERBA-2, or human homologue of ret-
roviral ERBA protein (avian erytroblastic leukemia viral
oncogene). Interestingly, homozygous knock-out mice
had an elevated level of thyroid-stimulating hormone
[74, 75]. However, the responsible genes for THRB
remain largely unknown (see Fig. 1, c).
VDR. Vitamin D3 receptor (NP_000367, OMIM
*601769, gene is localized to chromosome 12q12-14,
protein consists of 427 amino acids). VDR possesses
Zn-finger in its N-terminal domain. This part of protein
binds to general transcription factor II B (TFIIB) [76].
It was shown quite long ago that the VDR-depen-
dent gene regulation is blocked in B cells (peripheral
blood cells and LCLs) [77]. The active VDR pathway
could inhibit proliferation and enhance differentiation
of leukemic cells [78]. The level of VDR expression (at
mRNA and protein levels) was lower in the EBV trans-
formed cells compared to tonsil B cells [78].
Recently an anti-tumor effect was proposed for vita-
min D and VDR (for review see [79, 80]) (see Fig. 1, c).
CLUSTERS OF NUCLEAR RECEPTORS
We have analyzed the targeted nuclear receptors,
and grouped them into clusters. A phylogram is pre-
sented on Fig. 2.
ERBA
ERA
ERB
THRB
RARA
RXRA
RXRB
Nr2F2 Nr2F1
Nr4A3
Nr4A1
Nr3C1
Nr1H3
VDR PPARG
RORC
Nr6A1
Fig. 2. Phylogram of 16 nuclear receptors that expressed
differently in naïve and EBV-infected B-cells
Cluster of Nr2F proteins (COUP transcription
factors). These two proteins are the most closely relat-
ed among all of the discussed receptors. The alignment
score is 87 (Clustal W). Nr2F1 is downregulated but
Nr2F2 is upregulated. Unfortunately, not much is known
about these receptors. It is only known that Nr2F2 is
involved in Notch signaling repression (see Fig. 1, a). It
is important to continue the study on Nr2F2 receptor,
because Notch pathway is used by EBV upon latency
establishing: EBNA-2 and EBNA-3 family proteins regu-
late the expression of Notch-dependent genes.
Cluster of RXR proteins. These two receptors
have alignment score of 69, it is just little lower than for
THR and v-ERBA-77 (see the phylogenetic tree, Fig. 2).
Experimental Oncology 31, 67–73, 2009 (June) 71
The most interesting their feature is the ability to bind
Z-protein of EBV and inhibit its transcriptional activity,
i.e. prevent reactivation of the lytic cycle (see Fig. 1, d).
That makes RXR proteins the important players in the
control on latency.
Cluster of NUR 77 family proteins. These proteins
showed quite high alignment score — 47. Interestingly,
NF-κB activates NOR1 and can both downregulate and
upregulate NUR77 transcription (see Fig. 1, b). It was
shown earlier that both receptors can regulate apop-
tosis. However, the cell fate depends on the delicate
balance between them. EBNA-2 binds to NUR77, and
this binding blocks apoptosis [66, 67].
Cluster of estrogen receptors. The alignment
score for ER-α and ER-β is not very high — 44. In con-
trast to the first two clusters, both estrogen receptors
(α and β) are downregulated in the EBV-infected cells
and LCLs (see Fig. 1, e). No data on EBV-infected cells
were reported yet.
Both ERs can be regulated by AhR/Arnt heterodi-
mer in the absence of ligand, which is the fascinating
link to the role of ERs in the EBV induced transforma-
tion. Recently, we have shown that EBNA-3 could bind
AhR and the nuclear fraction of AhR was enriched in
the presence of EBNA-3 [81]. It is likely that EBNA-3
family proteins may interfere with ERs. This hypothesis
should be further elucidated.
Next cluster includes all of other receptors
(see Fig. 1, c). All of the 16 proteins discussed here
share common features — they possess C4 zinc finger
of nuclear hormone receptor (smart 00399, ZnF_C4)
and the ligand-binding domain of nuclear receptors
(smart 00430, HOLI). All of them are homologues to
v-ERBA with different score of alignment (highest —
THR, score of 77; lowest — GCCR, score of 16).
THE INTERSECTION OF NUCLEAR
RECEPTOR PATHWAYS
As we have already mentioned, we have determined
a set of nuclear receptors that are up- (and down-)
regulated in the latency III infected cells [10]. Some
receptors were shown before to be implicated in the
EBV biology, like NUR77, RXRA, RXRB, RARA, and
GCCR. Other proteins were not connected to lym-
phoblasts — MINOR, TF COUP I and II, ER-α and -β,
PPARG, RORC, LXRA, THRB, VDR, and GCNF. The
important role of the regulation of the expression of
nuclear receptors in transformation process may be
concluded from the fact that many of them can control
transcription of genes involved in B cell activation or
apoptosis. For example, upregulated GCNF gene can
activate B cell specific transcription factors Pax2/5 and
Gbx2 that specifically induce IL-6 [17, 18].
We have to mention that data obtained in our study
[10] show a correlation with the literature data. For
instance, others [30, 33] and we [10] have shown
that CD40 ligand downregulated PPARG, which can
induce apoptosis in B cells. Importantly, PPARG was
downregulated in the EBV-infected cells and LCLs
[10]. Moreover, not only protein level was changed, but
a cellular distribution of PPARG in the naïve, activated
and infected cells as well. As we discussed earlier, the
NFκB pathway becomes activated upon EBV-induced
transformation. From the other hand, it was reported
that PPARG binding to RelA resulted in the nuclear
export of RelA, thus inhibiting NF-κB pathway [31].
Noteworthy, EBV decreased mRNA level of PPARG and
changed the cellular distribution of PPARG [10].
It is important to notice that the ERs (both, -α
and -β) have an ERRE in the promoter region of RARA
gene. This makes them an important target to study in
the process of EBV-induced transformation.
Also, we have found that there is a crosstalk be-
tween RARA and GCCR. RARA binds the Z lytic protein
of EBV, and this binding prevents re-activation of the
lytic cycle in the latency III cells. RXRA and RXRB bind
Z protein too: one of them is upregulated and other
is downregulated by EBV (see Fig. 1). Probably, EBV
delicately regulates the levels of these receptors to
achieve the optimal expression of the target genes
involved in the B cell transformation.
Summarizing, we can conclude that there is a wide
unexplored area of the role of nuclear receptors that
might be involved in EBV-induced B cell transforma-
tion. Extensive study of cellular nuclear receptor
pathways is needed to fully understand their role in the
process of malignant cell transformation.
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Copyright © Experimental Oncology, 2009
|
| id | nasplib_isofts_kiev_ua-123456789-135697 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T18:45:18Z |
| publishDate | 2009 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Yenamandra, S.P. Klein, G. Kashuba, E. 2018-06-15T14:00:35Z 2018-06-15T14:00:35Z 2009 Nuclear receptors and their role in epstein — barr virus induced b cell transformation / S.P. Yenamandra, G. Klein, E. Kashuba // Experimental Oncology. — 2009. — Т. 31, № 2. — С. 67-73. — Бібліогр.: 81 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/135697 Epstein — Barr virus (EBV) is a lymphotropic virus that infects more than 90% of the human population, and targets B cells for
 infection. Infection of human B cells leads to the malignant transformation and eventual immortalization. In latency III infection
 six EBV-encoded nuclear antigens (EBNAs) and three latent membrane proteins (LMPs) are expressed in the transformed cells
 that can grow as a lymphoblastoid cell lines in vitro. These proteins hijack the normal B cell growth pathways by activating the
 constitutive growth promotion and external survival signals. We have determined a set of the nuclear receptors that are up- (and
 down-) regulated in the latency III infected cells at the mRNA level. In the present paper we discussed the possible role of these
 receptors in B cell transformation upon EBV infection based on the literature data. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Nuclear receptors and their role in epstein — barr virus induced b cell transformation Article published earlier |
| spellingShingle | Nuclear receptors and their role in epstein — barr virus induced b cell transformation Yenamandra, S.P. Klein, G. Kashuba, E. Reviews |
| title | Nuclear receptors and their role in epstein — barr virus induced b cell transformation |
| title_full | Nuclear receptors and their role in epstein — barr virus induced b cell transformation |
| title_fullStr | Nuclear receptors and their role in epstein — barr virus induced b cell transformation |
| title_full_unstemmed | Nuclear receptors and their role in epstein — barr virus induced b cell transformation |
| title_short | Nuclear receptors and their role in epstein — barr virus induced b cell transformation |
| title_sort | nuclear receptors and their role in epstein — barr virus induced b cell transformation |
| topic | Reviews |
| topic_facet | Reviews |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/135697 |
| work_keys_str_mv | AT yenamandrasp nuclearreceptorsandtheirroleinepsteinbarrvirusinducedbcelltransformation AT kleing nuclearreceptorsandtheirroleinepsteinbarrvirusinducedbcelltransformation AT kashubae nuclearreceptorsandtheirroleinepsteinbarrvirusinducedbcelltransformation |