1. Introduction
Protein phosphorylation is an essential post-translational modification of proteins in most cellular processes, and also in viral replication as well as in virally induced neoplastic transformation. This post-translational modification is achieved by about 518 different protein kinases expressed in eukaryotic cells [1]. Among these kinases, protein kinase CK2 (formerly known as casein kinase 2) is responsible for about 25% of the cellular phosphoproteome [2]. CK2 is a ubiquitously expressed serine/threonine protein kinase composed of two catalytic subunits (α or its isoform α’) and two non-catalytic β subunits [3], which form the tetrameric holoenzyme. CK2α and CK2α’ are also active as kinases in the absence of CK2β [4,5]. CK2α and CK2α’ share some common functions but they also have unique functions [6,7,8,9]. The substrate specificity varies for the holoenzyme and the individual CK2α and CK2α’ subunits [8]. In addition to the protein kinase activity, the CK2 subunits bind to numerous cellular and viral proteins [10]. These protein–protein interactions are implicated in targeting CK2 subunits or the holoenzyme to specific target proteins in different cellular compartments [10,11]. The binding of CK2β to other protein kinases appears to play a role in the regulation of these kinases such as A-raf, c-mos, p90rsk (for review see: [12]), PKC [13] or CHK-1 [14]. CK2 is a regulator of the PI3K/Akt, NF-κB, Wnt/β-catenin and JAK/STAT signaling cascades [15,16,17,18,19,20]. CK2 phosphorylates serine or threonine residues in a consensus sequence S/T-x-x-E/D/pS/pT, where x can be any amino acid with the exception of proline [21]. This consensus sequence is often found in an acidic environment. CK2, which has more than 500 known substrates [22], phosphorylates and thereby modulates the activities of viral and cellular proteins [23]. CK2 substrates include proteins involved in the regulation of gene expression or protein synthesis. Other substrates are implicated in cell growth, proliferation, survival or metabolic processes [22,24,25]. CK2 is associated with a high proliferation rate. It is therefore not surprising that this kinase also plays a role in the formation of virally induced tumors. Moreover, CK2 expression and protein kinase activity are higher in a variety of solid tumors compared to the normal tissue or cells [26]. The first experiments to demonstrate an oncogenic potential of CK2 date back to 1995, when Seldin and Leder showed that overexpression of the catalytic subunit of CK2 together with myc was capable of transforming lymphocytes [27]. This property of CK2 renders the kinase a suitable target for therapeutic treatment of tumor patients. Over the last decade, a great number of different inhibitors for the kinase activity of CK2 have been established [28,29,30,31]. Most of these inhibitors are ATP competitive inhibitors, although other inhibitors have also been introduced [32]. Comprehensive descriptions of CK2 inhibitors can be found in a number of reviews [30,33,34,35,36]. Recently, Wells et al. described a new CK2 inhibitor, which is highly CK2 specific and which did not influence the proliferation of cancer cells [31]. The role of this new CK2 inhibitor in viral replication and virally induced cell transformation awaits further analysis. Initially, phosphorylation by CK2 was demonstrated for the human papilloma virus E7 protein [37]. Later, it was shown that CK2 plays a role in infectious diseases caused by adeno viruses [38], hepatitis C virus (HCV) [39], human cytomegalovirus (HCMV) [40], human immunodeficiency virus (HIV) [41], human T-lymphotropic virus type 1 (HTLV-1) [42], human papilloma virus (HPV) [43], herpes simplex-1 virus (HSV) [44], SARS-CoV-2 [45] and also by Epstein–Barr virus (EBV) [46].
2. Epstein–Barr Virus
It has been known for many years that viruses account for about 10–15% of all cancer cases world-wide [47,48]. Epstein–Barr virus (EBV) was first discovered in continuously growing tumor cells derived from patients with Burkitt’s lymphoma [49]. EBV infects B cells of the immune system and epithelial cells. After the initial lytic infection, most likely in oropharyngeal epithelial cells, EBV latently persists in memory B cells for the rest of the infected individual’s life [50,51]. After infection, the linear viral DNA circularizes due to the cellular repair mechanism that joins free DNA ends. The viral genome remains in the nucleus as a circular episome. EBV infection in early childhood mostly takes place sub-clinically. Infected B-cells, when passing the germinal center (GC), may convert into functional memory cells; when the memory is recalled by contact with antigen, the cells mature into plasma cells and thereby shed both antibodies and virus. The resting memory B-cells do not express EBV proteins but various non-coding miRNAs and the so-called EBER RNAs. This type of infection is called latency 0 [52]. In endemic Burkitt’s lymphoma, the viral nuclear antigen 1 (EBNA-1), the non-coding EBER1 and EBER2 RNAs, the so-called BART miRNAs as well as a viral snoRNA are expressed (latency I). In Hodgkin’s disease (HD), diffuse large B-cell lymphoma (DLBCL), nasal NKT- cell lymphoma (NKTL), nasopharyngeal carcinoma (NPC) and gastric cancer (GC), the latent membrane proteins LMP1, LMP2A and LMP2B are expressed in addition to EBNA-1 and the non-coding RNAs mentioned above (latency II). LMP1 induces tumors in transgenic animals [53,54] as a co-carcinogen [55] and has transforming potential in tissue culture [56]. LMP1 mimics the CD40 molecule [57]. LMP2A blocks the B cell receptor (BCR) [58] and can functionally replace BCR [59]. Both LMP1 and LMP2A can activate cellular signaling pathways such as the PI3K/Akt, NF-κB, Wnt and JAK/STAT pathways [60,61,62,63]. In a cord-blood humanized mouse model, LMP1 and LMP2A cooperate in the generation of EBV-induced B cell lymphoma [64].
Under immunosuppression after organ transplantation or HIV infection, EBV-infected B-lymphocytes may grow out. The tumor cells in the so-called post-transplant lymphoproliferative disease (PTLD) express the full set of latent proteins including the LMPs, the EBV nuclear antigens 1–6 and all non-coding RNAs, including the so-called BHRF1 miRNAs that are expressed from the 3′UTR of the BHRF1 mRNA [65] (latency III) (Table 1).
Multiple sclerosis (MS) appears to be a multi-factorial disease [66], with EBV being the indispensable trigger [67]. The infection of adolescents or adults may lead to infectious mononucleosis [68], which increases two-fold the probability for the subsequent induction of multiple sclerosis [69]. Elevated antibody titers to the EBV nuclear antigen 1 (EBNA-1) often precede the onset of MS [70]. Cross- reactive antibodies to EBNA-1 acerbate the immune reaction to glial cells [71]. Vitamin D deficiency also plays an important role in MS [72]. EBNA-1 binds CK2, which might interfere with the maintenance of vitamin D levels in the infected cells. Elevated levels of CK2 are not only found in many types of cancer but may function in reducing the levels of the cancer-preventing vitamin D [73].
The infection with EBV, at least as a cofactor in the induction and possibly the maintenance in the various tumors, may be assumed: nasopharyngeal carcinoma has a strong geographic and viral (EBV) component as virtually all undifferentiated NPC are EBV positive [74]. The presence of EBV in various tumors of B- and T-cells as well as ones of epithelial origin has been established [75]. First detected in endemic Burkitt’s lymphoma, EBV was subsequently found in various lymphoma such as Hodgkin’s disease (HD), diffuse large B-cell lymphoma (DLBCL), and in virtually all cases of nasal/NK T-cell lymphoma (NKTL) [76]. The virus is also present in about 15% of gastric carcinoma (GC) cases, which are as NPC of epithelial origin [75].
In vitro, EBV readily transforms resting B-lymphocytes into permanently growing cell lines (LCLs), which express the full complement of so-called “latent” genes [77], including the BART and the BHRF1 miRNAs. These lymphoblastoid cell lines (LCLs) are the in vitro complement of the PTLDs that occur in immune-compromised patients. Depending on the type of tumor, different latent genes are expressed. In Burkitt’s lymphoma (BL, latency I), EBNA-1 is the only detectable EBV protein in addition to the non-(protein)-coding EBER RNAs and the BART microRNAs. A possible direct role in tumorigenesis has been suggested by the induction of EBNA-1-bearing tumors in transgenic mice [78], a supposition that was challenged, however, by a subsequent report that used the same mouse strain [79]. The EBER transcripts are present in all EBV-positive tumors and inhibit interferon-α-mediated apoptosis, possibly via the phosphorylation of eukaryotic initiation factor α (eIF2α) by PKR [80]. The proposition that interferon synthesis was inhibited via EBER/PKR was, however, subsequently challenged [81]. EBV encodes 44 miRNAs (
The EBV early protein EB-2, also known as BMLF1, Mta or SM protein, is expressed in the initial phase of lytic replication [85,86].
3. Phosphorylation of EBV Proteins by Protein Kinase CK2
Epstein–Barr nuclear antigen 1 (EBNA-1) is required for the replication of the EBV genome as an extra-chromosomal element and is a key transcriptional regulator of EBV latent gene expression [87]. EBNA-1 is indispensable for the immortalization of B-lymphocytes and is present in all EBV associated tumors [88]. The EBNA-1-mediated disruption of PML bodies is an important factor for the development of gastric cancer [89] and nasopharyngeal carcinoma (NPC) [90]. Through affinity chromatography and tandem affinity purification (TAP), each CK2 subunit was found to associate with EBNA-1 [91]. Sivachandran et al. showed that EBNA-1 binds to the CK2β subunit and CK2α appears to be tethered via CK2β to EBNA-1 [92]. A KSSR motif on the polypeptide chain of CK2β near the CK2β dimerization domain represents the interacting sequence for the binding to EBNA-1 [93]. EBNA-1 is a phosphoprotein [94,95]. It contains at least three putative CK2 phosphorylation sites. To our knowledge, CK2 phosphorylation of EBNA-1 has not been shown so far. One might speculate that EBNA-1 targets CK2 to other cellular proteins to induce their phosphorylation.
One of the target proteins appears to be the promyelocytic leukemia nuclear bodies (PML-NB). EBNA-1 disrupts the tumor-suppressive PML-NB, leading to an impaired DNA repair and an increased cell survival [96]. EBNA-1 and in particular its association with CK2, is necessary for the disruption of PML-NB by degradation of the PML proteins upon phosphorylation [97,98]. CK2 phosphorylates PML at serine 517, which leads to its polyubiquitylation and degradation [97,98]. Phosphorylation of EBNA-1 at the CDK phosphorylation site serine 393 [99] is critical for the interaction of EBNA-1 with PML proteins as well as for their degradation [93]. EBNA-1 mutants, which are defective for the binding of CK2 had a decreased ability to induce PML degradation.
EBNA1 is essential for the maintenance of the viral episome. In the dividing tumor cell, the viral DNA is replicated synchronously with the cellular DNA and evenly distributed to the daughter cells via EBNA-1, which tethers the viral DNA to the mitotic cellular DNA. Phosphorylation of serine(s) next to a stretch of methylated arginines within an arginine–glycine (RG) repeat is important for the segregation of the viral genome to the daughter cells during mitosis [100].
In 1992, EBNA-2 was identified as a substrate for CK2 and the phosphorylation sites were found to be serine 469 and serine 470 [101] (Table 2). EBNA-2 binds to the heterogeneous ribonucleoprotein –K (hnRNP-K) and this binding leads to an enhanced expression of LMP2A [102]. Interestingly, hnRNP-K also interacts with CK2β and the immediate-early protein 2 of human herpes virus 6 (HHV-6) [103]. Herpes virus-1 (HSV-1) infection stimulates the CK2 activity and the redistribution of CK2 from the nucleus to the cytoplasm. Furthermore, CK2 is complexed with the immediate-early protein IE63, also known as ICP27, of HSV-1. Likewise, CK2 binds and phosphorylates hnRNP-K [44,104,105]. It would be an interesting question whether EBV infection would also stimulate CK2 kinase activity, cytoplasmic localization and phosphorylation of hnRNP-K. The RG-repeat of EBNA-2 confers binding to EBNA-2-regulated promoters [106,107,108]. It is therefore possible that DNA binding of both, EBNA-1 and EBNA-2, is regulated by simultaneous phosphorylation and arginine methylation.
The latent membrane protein 1 (LMP1), expressed in type II and III latency, is a transforming protein ([109] and reviewed in [110]) (Table 1). LMP1 consists of 386 amino acids. It is an integral membrane protein with a C-terminal cytoplasmic tail, which is engaged in intracellular signal transduction [111]. The C-terminus contains two trans-activating regions (CTARs), one is located between amino acids 194–232 (CTAR1), which also harbors the CK2 phosphorylation sites and which is known to activate the NF-κB signaling pathway [112] and the PI3K/Akt pathway [113]. Chi et al. reported that CK2 phosphorylates LMP1 at least in vitro [92] (Table 2). Using bacterially expressed fragments of LMP1 revealed that the C-terminus harbors CK2 phosphorylation site(s). Later, serine residues at position 211 and 215 of LMP1 were determined as substrates for CK2 in vitro [114]; at least serine 215 of LMP1 was also found to be phosphorylated in human cell lines. The observation that serine 211 is only phosphorylated in the presence of phospho-serine 215 points to a hierarchical phosphorylation, which was reported for other proteins by Litchfield and co-workers [115]. The functional consequence of the CK2 phosphorylation of LMP1, however, remains to be elucidated.
The ZEBRA protein, also known as EB-1, Zta or BZLF1, is another EBV-encoded protein which plays a role in the disruption of viral latency and the initiation of the viral lytic cycle [46]. ZEBRA, a member of the bZIP family, binds to DNA to initiate viral replication where it functions as a transcription factor. It is a multifunctional protein that also binds to cellular and viral proteins. Serine 167 and serine 173 were mapped as in vivo and in vitro CK2 phosphorylation sites [116,117] (Table 2). By mutating the CK2 phosphorylation sites into alanine and also through the inhibition of the CK2 kinase activity, it was shown that the CK2 phosphorylation of ZEBRA leads to impaired DNA binding activity [116,118].
The EBV early protein 2 (EB-2, also known as BMLF1, Mta or SM) is responsible for the nuclear export of a subset of early and late viral mRNAs and for the production of infectious viruses [119]. EB-2 was detected as a phosphoprotein in EBV-infected cells. It can be phosphorylated by CK2 at least in vitro [120]. Furthermore, MALDI-TOF analysis and co-immunoprecipitation experiments showed that CK2α and CK2β subunits co-purify with EB-2. Mutant analysis with EB-2, where the CK2 phosphorylation sites were replaced by non-phosphorylatable alanine residues, revealed that the CK2 phosphorylation of at least one of the serine residues 55, 56 and 57 of EB-2 is critical for the production of infectious virus [121,122] (Table 2).
Table 2CK2 phosphorylation of EBV proteins.
| Protein | Phosphorylated Amino Acid | Reference |
|---|---|---|
| EBNA-2 | 469, 470 | [101] |
| LMP1 | 211, 215 | [92,114] |
| EB-1 (ZEBRA) | 167, 173 | [116,117] |
| EB-2 (SM) | 55, 56, 57 | [121] |
4. CK2 and Cellular Proteins in the Balance between Lytic EBV Virus Replication and Cell Transformation
4.1. Ikaros and the Switch from EBV Latency to Lytic Replication
Ikaros is a zinc finger, DNA-binding transcriptional regulator [123]. Functions of Ikaros are regulated by post-translational modifications such as phosphorylation and sumoylation [124,125,126,127]. CK2 phosphorylates Ikaros at multiple sites [128,129,130]. In particular, the N-terminal CK2 phosphorylation of Ikaros reduces its DNA binding affinity and thereby its transcription factor activity [131]. The role of CK2 in the regulation of the transcriptional activity of Ikaros has very recently been reviewed by Bogush et al. [132]. It was shown that Ikaros plays a role in the maintenance of viral latency in EBV-positive Burkitt’s lymphoma [133]. So far it has not been directly shown, but it is tempting to speculate, that the CK2 phosphorylation of Ikaros might play a role in the Ikaros-mediated switch from latency to lytic replication of EBV.
4.2. CK2 Binding Cellular Protein ARKL1 and the Regulation of EBV Replication
EBV maintains a life-long infection in humans through a switch between a latent and a lytic replication cycle [68]. The ARKADIA-like-1 (ARKL1) protein acts as a negative regulator of EBV reactivation for a lytic infection by interacting with c-jun. The silencing of CK2β abrogates the ARKL1 c-jun interaction and thereby EBV reactivation [134]. This function is explained by the fact that EBNA-1 binds to the same KSSR motif in the polypeptide chain of CK2β rather than ARKL1 [93]. There is increasing evidence that ARKL1 has a more general anti-viral function because it was shown that it also inhibits influenza virus infection [135] and human T-cell leukemia virus type 1 (HTLV-1) infection [136].
4.3. CK2 and the Autoregulatory Loop between NF-κB, BARTs and LMP1
BARTs are expressed in all types of EBV-infected cells and in EBV-associated tumors [137,138]. High levels of BARTs are associated with the maintenance of the oncogenic state of NPC. The NF-κB family of transcription factors plays an essential role in inflammation and cancer initiation and progression [139]. Several members of the NF-κB activation cascade are phosphorylated by CK2 and thereby activated for transactivation [140]. NF-κB regulates the expression of BARTs, which repress LMP1 expression. Furthermore, LMP1 is implicated in the activation of the NF-κB signaling cascade. This autoregulatory loop seems to regulate the balance between lytic proliferation and cell transformation [141] (Figure 1).
5. Common Targets of EBV and CK2
5.1. EBV, CK2 and the NF-κB Pathway
EBV is thought to exert its oncogenic potential via different cellular signaling pathways, including the NF-κB signaling pathway [142]. LMP1 enhances the NF-κB signaling and activates NF-κB transcription factor activity [65]. NF-κB is a transcription factor complex consisting of p50, p52, RelAp65, RelB and RelC subunits. For the immortalization of EBV-infected cells, LMP1 activates RelAp65 to bind to the human telomerase reverse transcriptase (hTERT) to activate telomerase and thereby induce EBV-mediated immortalization. It has been known for quite some time that CK2 regulates the NF-κB pathway through the phosphorylation of several components of this pathway, such as RelAp65, IκB, IKK2 and NF-κB [143,144,145,146,147] (Figure 1). In the nucleus, CK2 binds to and phosphorylates RelAp65 at serine 529 [148]. The CK2 phosphorylation of IκB promotes its degradation and thereby NF-κB activation. In vitro phosphorylation experiments have shown that CK2 phosphorylates IKK2. The inhibition of CK2 kinase activity with apigenin- or siRNA-targeting CK2β completely inhibited IKK2 phosphorylation [149] and NF-κB activity. The incubation of IKK2 with recombinant CK2α leads to an increased activity of IKK2 for the phosphorylation of serine 32 and serine 36 in the N-terminus of IKBα. On the other hand, CK2 promotes the IKK-mediated activation of NF-κB [149]. As mentioned above, LMP1 is phosphorylated by CK2 [92,114]. It remains, however, to be elucidated whether the CK2 phosphorylation of LMP1 is necessary for the stimulation of the NF-κB signaling cascade (Figure 1).
5.2. EBV, CK2 and the PI3K/Akt Pathway
Another signaling pathway that is implicated in EBV-mediated cell transformation is the PI3K/Akt signaling pathway (Figure 2). LMP1 and LMP2A activate PI3K [150,151]. The PI3K/Akt signaling pathway plays a major role in cancer development [152]. PI3K is upstream regulated by the phosphatase and tensin homologue (PTEN) and regulates downstream Akt kinase, also known as protein kinase B (PKB). PTEN converts phosphatidylinositol-3,4,5-triphosphate (PIP3) into phosphatidylinositol-4,5-bisphosphate (PIP2). CK2 phosphorylates PTEN at serine 370, serine 380, threonine 382, threonine 383 and serine 385, which results in an increase in PTEN protein stability [153]. Miller et al. found that serine 370 and serine 385 are the main CK2 phosphorylation sites, which are responsible for the inhibition of the phosphatase activity of PTEN for its substrate PIP3 and the inhibition of the caspase-3 cleavage of PTEN [153,154]. Thus, CK2 phosphorylation of PTEN leads to an elevated protein stability of PTEN and PTEN inactivation [155]. The inhibition of CK2 by CX-4945 reverses PTEN stabilization, which leads to an elevated cell death by an inhibition of the PI3K/Akt pathway. CK2 phosphorylates GSK3β, which also phosphorylates PTEN [156] in a cooperative way; i.e., CK2 phosphorylation at serine 370 strongly enhances the subsequent phosphorylation at threonine 366 by GSK3β [157]. The threonine 366 phosphorylation leads to destabilization of PTEN. However, this appears to be a cell type specificity of the phosphorylation events [157,158]. Akt phosphorylates GSK3β and this results in an inhibition of GSK3β (Figure 2).
The EBV-mi-Bart7-3p is highly expressed in nasopharyngeal carcinoma (NPC) and positively correlated with lymph node metastasis and the clinical stage of NPC [159]. miR-Bart7-3p promotes the transition from the epithelial to the mesenchymal phenotype by regulating PTEN/PI3K/Akt, GSK2β, Snail and β-catenin. Snail is tightly regulated at the transcriptional and post-transcriptional levels. The GSK3β phosphorylation of Snail regulates Snail protein stability and nuclear export [160]. Furthermore, CK2 in vitro and in vivo phosphorylates Snail at serine 92. By using a yeast two hybrid screen, pull-down assays and co-immunoprecipitation analysis, CK2 was identified as a binding partner of Snail. By replacing serine against the non-phosphorylatable alanine, it was shown that the CK2 phosphorylation at serine 92 of Snail is required for the efficient transcriptional repression of E-cadherin. Furthermore, serine 92 phosphorylation appears to increase Snail degradation [160] (Figure 2).
Furthermore, LMP1 downregulates the expression of PTEN by enhancing the expression of miR-21, thereby activating the PI3K/Akt pathway [161]. LMP1 also activates the PI3K/Akt pathway and the HIF1α signaling in EBV positive nasopharyngeal carcinomas (NPCs) facilitating vascularization of the tumor [162]. LMP1 interacts with the p85 subunit of PI3K, which leads to an activation of src. Src enhances the activity of the interferon regulatory factor 4 (IRF4) and thereby promotes cell transformation [163].
5.3. EBV, CK2 and the Wnt/β-Catenin Pathway
Wnt signaling is another pathway which is implicated in the EBV-induced cell transformation [164] (Figure 3). Activation of the Wnt signaling pathway leads to an increase in cell survival and a reduction in apoptosis [85]. CK2 is implicated in Wnt signaling through its association with and its phosphorylation of Dishevelled (Dvl), which is in a multi-protein complex containing β-catenin. CK2 phosphorylates β-catenin and thereby promotes its stability and translocation into the nucleus [165,166]. The inhibition of CK2 by TBBt leads to an even intracellular distribution of Dishevelled and inhibits a further phosphorylation by CK1ε and thereby an activation of TCF/LEF-mediated transcription [167] (Figure 3). Moreover, CK2 phosphorylates Akt at serine 129 [18,168,169]. This CK2 phosphorylation appears not to be an on or off signal but to increase the activity of the Akt kinase. CK2 phosphorylation at serine 129 hyperactivates Akt for the phosphorylation of β-catenin at serine 552, which promotes its nuclear accumulation and transcriptional activation. In addition, CK2 itself phosphorylates β-catenin at threonine 393, which protects β-catenin from proteasome-dependent degradation and increases its transcriptional activity [165].
5.4. EBV, CK2 and the Janus Kinase/Signaling Transduction and Transcription Activator (JAK/STAT) Pathway
The tyrosine kinases of the JAK family are either activated by growth factors and cytokines or as the result of mutations [170]. In EBV-positive diffuse large B-cell lymphoma (DLBCL), there is some indication that the JAK/STAT pathway is activated [171]. LMP1 appears to trigger the JAK/STAT pathway by the regulation of the JAK3 expression as well as the phosphorylation of STAT [172]. CK2 is an interaction partner of the JAKs and essential for the activation of the JAK/STAT pathway [170]. CK2 phosphorylates STAT1 [173] and STAT3 [174] and also JAK2 and JAK3 [170], which results in an amplification of cytokine signals [170,175]. CK2 itself is under the control of STAT3 [176], which might indicate an auto-regulatory loop. Co-immunoprecipitation experiments have revealed that CK2α and CK2β bind to JAK1 and JAK2. The expression of cytokine signaling 3 (SOCS-3) is inhibited by siRNA technology targeting CK2 or by pharmacological inhibition of the enzyme activity of CK2 [170] (Figure 4).
6. EBV-Encoded LMP1 Protein and p53
p53 is a tumor suppressor which regulates the eukaryotic cell cycle and apoptosis (for review see: [177]). Since viruses depend on host cells for their replication, the guardian of the genome p53 [178] plays a central role in the host defense against a virus infection [179]. It was shown that an EBV infection interferes with cell cycle checkpoint control [180,181] and affects p53 stability [180,182]. There was a controversy whether LMP1 represses DNA repair by p53 and inactivated the transcriptional activity of p53 [183] or whether it activates p53 transcriptional activity and increases the stability of p53 through multi-sites phosphorylation [184,185]. In another study, it was shown that the overexpression of LMP1 led to a poly-ubiquitination of p53 followed by a decrease in p53 levels [186]. p53 is phosphorylated by different protein kinases, including CK2, and it is associated with CK2 [187,188,189,190]. The phosphorylation of p53 by CK2 at serine 392 leads to the stabilization of p53 protein [191], indicating that this phosphorylation might counteract LMP1 activity.
7. Conclusions
In the present review, we demonstrated that protein kinase CK2 is strongly implicated in the regulation of EBV viral replication, in persistent infection and in cell transformation leading to cancer. These different functions are achieved through the phosphorylation of virally encoded proteins as well as through the phosphorylation of cellular proteins, which are regulators of cellular signaling pathways such as the NF-κB, PIP3/Akt, JAK/STAT, and Wnt/Dishevelled/β-catenin signaling pathways. CK2 and EBV act on the same cellular signaling pathways. It remains to be elucidated whether and how EBV hijacks CK2 to influence these different signaling pathways for neoplastic transformation. The binding of CK2 subunits to viral and cellular proteins might reflect an enzyme–substrate interaction. Alternatively, the interactions might target CK2 to other substrates. Since a great number of different CK2 kinase inhibitors are now known, some of which have already been used to inhibit signaling pathways, these inhibitors are promising tools for the inhibition of virus replication as well as of virally induced cancers. Very recently, CK2 was found to play a role in SARS-CoV-2 infections [45]. The knowledge of the role of CK2 in EBV infection might also help to find new strategies to fight COVID-19 [192].
All three authors wrote and edited the manuscript. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
Not applicable.
The authors declare no conflict of interest.
| BARF1 | BamHI-A rightward open reading frame 1 |
| BARTs | BamHI-A rightward transcripts |
| BZLF1 or ZEBRA or EB-1 or Zta | BamHI-Z EBV replication activator |
| BL | Burkitt’s lymphoma |
| DLBCL | Diffuse large B-cell lymphoma |
| PKR | Double-stranded RNA-dependent protein kinase |
| EBER | Epstein–Barr encoded small RNA |
| EBV | Epstein–Barr virus |
| EBNA | Epstein–Barr virus nuclear antigen |
| GC | Gastric carcinoma |
| HCV | Hepatitis C virus |
| HSV | Herpes simplex-1 virus |
| HD | Hodgkin’s disease |
| HCMV | Human cytomegalovirus |
| HIV | Human immunodeficiency virus |
| HTLV-1 | Human T-lymphotropic virus type 1 |
| JAK | Janus kinase |
| LMP | Latent membrane protein |
| MS | Multiple sclerosis |
| NKTL | Nasal NK/T-cell lymphoma |
| NPC | Nasopharyngeal carcinoma |
| NF-kB | Nuclear factor kappaB |
| PI3K | Phosphatidylinositol-3-kinase |
| PTLD | Post-transplant lymphoproliferative disease |
| Akt | Protein kinase B, also known as Akt |
| CK2 | Protein kinase CK2 |
| PKC | protein kinase C |
| SARS-CoV-2 | Severe acute respiratory syndrome coronavirus type-2 |
| STAT | Signal transducer and activator of transcription protein |
Footnotes
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Enlarge this image.Figure 1. LMP1, BARTs, CK2 and the NF-κB signaling pathway. LMP1, NF-κB and BARTs are implicated in an autoregulatory loop. CK2 phosphorylates and thereby stimulates the NF-κB signaling pathway. As an activated transcriptional regulator, NF-κB increases the expression of BARTs and the expression of genes implicated in cell survival, proliferation and migration.
Enlarge this image.Figure 2. LMP1, miRNA-BART-3p and CK2 regulate the PI3K/Akt signaling pathway. CK2 phosphorylates PTEN, Akt and Snail to regulate the PI3K/Akt signaling pathway in order to induce proliferation, angiogenesis, cancer metastasis and epithelial and mesenchymal transition (EMT).
Enlarge this image.Figure 3. LMP1 and CK2 cooperate in the activation of the Wnt, Dishevelled and β-catenin pathway. CK2 phosphorylates and activates Wnt, Dishevelled and β-catenin to promote cell proliferation and a reduction in apoptosis.
Enlarge this image.Figure 4. LMP1 and CK2 cooperate in the activation of the JASK/STAT signaling pathway. CK2 binds to JAK and STAT and phosphorylates both proteins to promote proliferation and the immune response.
Latency type and expression of EBV transcripts.
| Gene(s)/Protein(s) Expressed in EBV Latency Patterns | ||||||||
|---|---|---|---|---|---|---|---|---|
| Latency Type | EBERs | BART miRNAs | EBNA1 | LMP1/2 | EBNA2-6 | BHRF1 |
v-snoRNA | Cell Type/ |
| 0 | + | + | Memory B-cell | |||||
| I | + | + | + | BL/GC B-cell | ||||
| II | + | + | + | + | HD/NPC/DLBCL | |||
| III | + | + | + | + | + | + | + | PTLD/LCLs |
Abbrevations: BL: Burkitt’s lymphoma; GC: germinal center; HD: Hodgkin’s disease; NPC: nasopharyngeal carcinoma; DLBCL: diffuse large B-cell lymphoma; BART: BamHI rightward transcript; BHRF1: BamHI rightward open reading frame 1; PTLD: post-transplant lymphoproliferative disease; LCL: lympoblastoid cell line.
References
1. Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science; 2002; 298, pp. 1912-1934. [DOI: https://dx.doi.org/10.1126/science.1075762] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12471243]
2. Meggio, F.; Pinna, L.A. One-thousand-and-one substrates of protein kinase CK2?. FASEB J.; 2003; 17, pp. 349-368. [DOI: https://dx.doi.org/10.1096/fj.02-0473rev] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12631575]
3. Litchfield, D.W. Protein kinase CK2: Structure, regulation and role in cellular decisions of life and death. Biochem. J.; 2003; 369, pp. 1-15. [DOI: https://dx.doi.org/10.1042/bj20021469]
4. Heriche, J.K.; Lebrin, F.; Rabilloud, T.; LeRoy, D.; Chambaz, E.M.; Goldberg, Y. Regulation of protein phosphatase 2A by direct interaction with casein kinase 2alpha. Science; 1997; 276, pp. 952-955. [DOI: https://dx.doi.org/10.1126/science.276.5314.952]
5. Stigare, J.; Buddelmeijer, N.; Pigon, A.; Egyhazi, E. A majority of CK2 alpha subunit is tightly bound to intranuclear compounds but not to the beta subunit. Mol. Cell. Biol.; 1993; 129, pp. 77-85.
6. Lou, D.Y.; Dominguez, I.; Toselli, P.; Landesman-Bollag, E.; O’Brien, C.; Seldin, D.C. The alpha catalytic subunit of protein kinase CK2 is required for mouse embryonic development. Mol. Cell. Biol.; 2008; 28, pp. 131-139. [DOI: https://dx.doi.org/10.1128/MCB.01119-07]
7. Xu, X.; Toselli, P.A.; Russell, L.D.; Seldin, D.C. Globozoospermia in mice lacking the casein kinase II α’ catalytic subunit. Nat. Genet.; 1999; 23, pp. 118-121. [DOI: https://dx.doi.org/10.1038/12729] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10471512]
8. Vilk, G.; Saulnier, R.B.; St Pierre, R.; Litchfield, D.W. Inducible expression of protein kinase CK2 in mammalian cells-Evidence for functional specialization of CK2 isoforms. J. Biol. Chem.; 1999; 274, pp. 14406-14414. [DOI: https://dx.doi.org/10.1074/jbc.274.20.14406]
9. Turowec, J.P.; Vilk, G.; Gabriel, M.; Litchfield, D.W. Characterizing the convergence of protein kinase CK2 and caspase-3 reveals isoform-specific phosphorylation of caspase-3 by CK2alpha’: Implications for pathological roles of CK2 in promoting cancer cell survival. Oncotarget; 2013; 4, pp. 560-571. [DOI: https://dx.doi.org/10.18632/oncotarget.948] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23599180]
10. Montenarh, M.; Götz, C. The interactome of protein kinase CK2. Protein Kinase CK2; Pinna, L.A. John Wiley & Sons, Inc.: Oxford, UK, 2013; pp. 76-116.
11. Faust, M.; Montenarh, M. Subcellular localization of protein kinase CK2: A key to its function?. Cell Tissue Res.; 2000; 301, pp. 329-340. [DOI: https://dx.doi.org/10.1007/s004410000256]
12. Guerra, B.; Issinger, O.G. Protein kinase CK2 and its role in cellular proliferation, development and pathology. Electrophoresis; 1999; 20, pp. 391-408. [DOI: https://dx.doi.org/10.1002/(SICI)1522-2683(19990201)20:2<391::AID-ELPS391>3.0.CO;2-N]
13. Bren, G.D.; Pennington, K.N.; Paya, C.V. PKC-zeta-associated CK2 participates in the turnover of free IkappaBalpha. J. Mol. Biol.; 2000; 297, pp. 1245-1258. [DOI: https://dx.doi.org/10.1006/jmbi.2000.3630] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10764587]
14. Guerra, B.; Issinger, O.G.; Wang, J.Y.J. Modulation of human checkpoint kinase Chk1 by the regulatory β-subunit of protein kinase CK2. Oncogene; 2003; 22, pp. 4933-4942. [DOI: https://dx.doi.org/10.1038/sj.onc.1206721]
15. Gray, G.K.; McFarland, B.C.; Rowse, A.L.; Gibson, S.A.; Benveniste, E.N. Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells. Oncotarget; 2014; 5, pp. 6484-6496. [DOI: https://dx.doi.org/10.18632/oncotarget.2248]
16. Wang, S.; Jones, K.A. CK2 controls the recruitment of Wnt regulators to target genes in vivo. Curr. Biol.; 2006; 16, pp. 2239-2244. [DOI: https://dx.doi.org/10.1016/j.cub.2006.09.034]
17. Gao, Y.; Wang, H.Y. Casein kinase 2 Is activated and essential for Wnt/beta-catenin signaling. J. Biol. Chem.; 2006; 281, pp. 18394-18400. [DOI: https://dx.doi.org/10.1074/jbc.M601112200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16672224]
18. Guerra, B. Protein kinase CK2 subunits are positive regulators of AKT kinase. Int. J. Oncol.; 2006; 28, pp. 685-693. [DOI: https://dx.doi.org/10.3892/ijo.28.3.685]
19. Ponce, D.P.; Yefi, R.; Cabello, P.; Maturana, J.L.; Niechi, I.; Silva, E.; Galindo, M.; Antonelli, M.; Marcelain, K.; Armisen, R. et al. CK2 functionally interacts with AKT/PKB to promote the beta-catenin-dependent expression of survivin and enhance cell survival. Mol. Cell. Biochem.; 2011; 356, pp. 127-132. [DOI: https://dx.doi.org/10.1007/s11010-011-0965-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21735093]
20. Ponce, D.P.; Maturana, J.L.; Cabello, P.; Yefi, R.; Niechi, I.; Silva, E.; Armisen, R.; Galindo, M.; Antonelli, M.; Tapia, J.C. Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent up-regulation of beta-catenin transcriptional activity. J. Cell. Physiol.; 2011; 226, pp. 1953-1959. [DOI: https://dx.doi.org/10.1002/jcp.22527] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21506126]
21. Marchiori, F.; Meggio, F.; Marin, O.; Borin, G.; Calderan, A.; Ruzza, P.; Pinna, L.A. Synthetic peptide substrates for casein kinase 2. Assessment of minimum structural requirements for phosphorylation. Biochim. Biophys. Acta; 1988; 971, pp. 332-338. [DOI: https://dx.doi.org/10.1016/S0005-2728(88)80048-3]
22. de Villavicencio-Diaz, T.; Rabalski, A.J.; Litchfield, D.W. Protein Kinase CK2: Intricate Relationships within Regulatory Cellular Networks. Pharmaceuticals; 2017; 10, E27. [DOI: https://dx.doi.org/10.3390/ph10010027] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28273877]
23. Rabjerg, M.; Bjerregaard, H.; Halekoh, U.; Jensen, B.L.; Walter, S.; Marcussen, N. Molecular characterization of clear cell renal cell carcinoma identifies CSNK2A1, SPP1 and DEFB1 as promising novel prognostic markers. APMIS; 2016; 124, pp. 372-383. [DOI: https://dx.doi.org/10.1111/apm.12519] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26876164]
24. Montenarh, M.; Götz, C. Protein kinase CK2 and ion channels. Biomed. Rep.; 2020; 13, 55. [DOI: https://dx.doi.org/10.3892/br.2020.1362]
25. Al-Quobaili, F.; Montenarh, M. CK2 and the regulation of the carbohydrate metabolism. Metabolism; 2012; 61, pp. 1512-1517. [DOI: https://dx.doi.org/10.1016/j.metabol.2012.07.011]
26. Ortega, C.E.; Seidner, Y.; Dominguez, I. Mining CK2 in cancer. PLoS ONE; 2014; 9, e115609. [DOI: https://dx.doi.org/10.1371/journal.pone.0115609]
27. Seldin, D.C.; Leder, P. Casein kinase II alpha transgene-induced murine lymphoma: Relation to theileriosis in cattle. Science; 1995; 267, pp. 884-897. [DOI: https://dx.doi.org/10.1126/science.7846532]
28. Cozza, G.; Pinna, L.A.; Moro, S. Protein kinase CK2 inhibitors: A patent review. Expert Opin. Ther. Pat.; 2012; 22, pp. 1081-1097. [DOI: https://dx.doi.org/10.1517/13543776.2012.717615] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22908959]
29. Sarno, S.; Salvi, M.; Battistutta, R.; Zanotti, G.; Pinna, L.A. Features and potentials of ATP-site directed CK2 inhibitors. Biochim. Biophys. Acta; 2005; 1754, pp. 263-270. [DOI: https://dx.doi.org/10.1016/j.bbapap.2005.07.043] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16198160]
30. Cozza, G. The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design. Pharmaceuticals; 2017; 10, E26. [DOI: https://dx.doi.org/10.3390/ph10010026]
31. Wells, C.I.; Drewry, D.H.; Pickett, J.E.; Tjaden, A.; Krämer, A.; Müller, S.; Gyenis, L.; Menyhart, D.; Litchfield, D.W.; Knapp, S. et al. Development of a potent and selective chemical probe for the pleiotropic kinase CK2. Cell Chem. Biol.; 2021; 28, pp. 546-558. [DOI: https://dx.doi.org/10.1016/j.chembiol.2020.12.013]
32. Prudent, R.; Cochet, C. New protein kinase CK2 inhibitors: Jumping out of the catalytic box. Chem. Biol.; 2009; 16, pp. 112-120. [DOI: https://dx.doi.org/10.1016/j.chembiol.2009.01.004] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19246001]
33. Cozza, G.; Pinna, L.A. Casein kinases as potential therapeutic targets. Expert Opin. Ther. Targets; 2016; 20, pp. 319-340. [DOI: https://dx.doi.org/10.1517/14728222.2016.1091883]
34. Cozza, G.; Zanin, S.; Sarno, S.; Costa, E.; Girardi, C.; Ribaudo, G.; Salvi, M.; Zagotto, G.; Ruzzene, M.; Pinna, L.A. Design, validation and efficacy of bisubstrate inhibitors specifically affecting ecto-CK2 kinase activity. Biochem. J.; 2015; 471, pp. 415-430. [DOI: https://dx.doi.org/10.1042/BJ20141127] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26349539]
35. Borgo, C.; Cesaro, L.; Hirota, T.; Kuwata, K.; D’Amore, C.; Ruppert, T.; Blatnik, R.; Salvi, M.; Pinna, L.A. Comparing the efficacy and selectivity of CK2 inhibitors. A phosphoproteomics approach. Eur. J. Med. Chem.; 2021; 214, 113217. [DOI: https://dx.doi.org/10.1016/j.ejmech.2021.113217] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33548633]
36. Borgo, C.; Ruzzene, M. Protein kinase CK2 inhibition as a pharmacological strategy. Adv. Protein Chem. Struct. Biol.; 2021; 124, pp. 23-46. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33632467]
37. Firzlaff, J.M.; Galloway, D.A.; Eisenman, R.N.; Luscher, B. The E7 protein of human papillomavirus type 16 is phosphorylated by casein kinase II. New Biol.; 1989; 1, pp. 44-53. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2562189]
38. Ching, W.; Dobner, T.; Koyuncu, E. The human adenovirus type 5 E1B 55-kilodalton protein is phosphorylated by protein kinase CK2. J. Virol.; 2012; 86, pp. 2400-2415. [DOI: https://dx.doi.org/10.1128/JVI.06066-11] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22190719]
39. Franck, N.; Le Seyec, J.; Guguen-Guillouzo, C.; Erdtmann, L. Hepatitis C virus NS2 protein is phosphorylated by the protein kinase CK2 and targeted for degradation to the proteasome. J. Virol.; 2005; 79, pp. 2700-2708. [DOI: https://dx.doi.org/10.1128/JVI.79.5.2700-2708.2005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15708989]
40. Alvisi, G.; Marin, O.; Pari, G.; Mancini, M.; Avanzi, S.; Loregian, A.; Jans, D.A.; Ripalti, A. Multiple phosphorylation sites at the C-terminus regulate nuclear import of HCMV DNA polymerase processivity factor ppUL44. Virology; 2011; 417, pp. 259-267. [DOI: https://dx.doi.org/10.1016/j.virol.2011.06.015]
41. Schubert, U.; Henklein, P.; Boldyreff, B.; Wingender, E.; Strebel, K.; Porstmann, T. The human immunodeficiency virus type 1 encoded Vpu protein is phosphorylated by casein kinase-2 (CK-2) at positions Ser52 and Ser56 within a predicted alpha-helix-turn-alpha-helix-motif. J. Mol. Biol.; 1994; 236, pp. 16-25. [DOI: https://dx.doi.org/10.1006/jmbi.1994.1114] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8107101]
42. Bidoia, C.; Mazzorana, M.; Pagano, M.A.; Arrigoni, G.; Meggio, F.; Pinna, L.A.; Bertazzoni, U. The pleiotropic protein kinase CK2 phosphorylates HTLV-1 Tax protein in vitro, targeting its PDZ-binding motif. Virus Genes; 2010; 41, pp. 149-157. [DOI: https://dx.doi.org/10.1007/s11262-010-0494-3]
43. Piirsoo, A.; Piirsoo, M.; Kala, M.; Sankovski, E.; Lototskaja, E.; Levin, V.; Salvi, M.; Ustav, M. Activity of CK2alpha protein kinase is required for efficient replication of some HPV types. PLoS Pathog.; 2019; 15, e1007788. [DOI: https://dx.doi.org/10.1371/journal.ppat.1007788] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31091289]
44. Koffa, M.D.; Kean, J.; Zachos, G.; Rice, S.A.; Clements, J.B. CK2 protein kinase is stimulated and redistributed by functional herpes simplex virus ICP27 protein. J. Virol.; 2003; 77, pp. 4315-4325. [DOI: https://dx.doi.org/10.1128/JVI.77.7.4315-4325.2003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12634389]
45. Bouhaddou, M.; Memon, D.; Meyer, B.; White, K.M.; Rezelj, V.V.; Marrero, M.C.; Polacco, B.J.; Melnyk, J.E.; Ulferts, S.; Kaake, R.M. et al. The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell; 2020; 182, pp. 685-712. [DOI: https://dx.doi.org/10.1016/j.cell.2020.06.034] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32645325]
46. Miller, G.; El-Guindy, A.; Countryman, J.; Ye, J.; Gradoville, L. Lytic cycle switches of oncogenic human gammaherpesviruses. Adv. Cancer Res.; 2007; 97, pp. 81-109.
47. Moore, P.S.; Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer; 2010; 10, pp. 878-889. [DOI: https://dx.doi.org/10.1038/nrc2961]
48. Martin, D.; Gutkind, J.S. Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene; 2008; 27, (Suppl. S2), pp. S31-S42. [DOI: https://dx.doi.org/10.1038/onc.2009.351]
49. Ooka, T. The molecular biology of Epstein-Barr virus. Biomed. Pharm.; 1985; 39, pp. 59-66.
50. Amon, W.; Farrell, P.J. Reactivation of Epstein-Barr virus from latency. Rev. Med. Virol.; 2005; 15, pp. 149-156. [DOI: https://dx.doi.org/10.1002/rmv.456]
51. Khan, G.; Miyashita, E.M.; Yang, B.; Babcock, G.J.; Thorley-Lawson, D.A. Is EBV persistence in vivo a model for B cell homeostasis?. Immunity; 1996; 5, pp. 173-179. [DOI: https://dx.doi.org/10.1016/S1074-7613(00)80493-8]
52. Qiu, J.; Cosmopoulos, K.; Pegtel, M.; Hopmans, E.; Murray, P.; Middeldorp, J.; Shapiro, M.; Thorley-Lawson, D.A. A novel persistence associated EBV miRNA expression profile is disrupted in neoplasia. PLoS Pathog.; 2011; 7, e1002193. [DOI: https://dx.doi.org/10.1371/journal.ppat.1002193] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21901094]
53. Wilson, J.B.; Weinberg, W.; Johnson, R.; Yuspa, S.; Levine, A.J. Expression of the BNLF-1 oncogene of Epstein-Barr virus in the skin of transgenic mice induces hyperplasia and aberrant expression of keratin 6. Cell; 1990; 61, pp. 1315-1327. [DOI: https://dx.doi.org/10.1016/0092-8674(90)90695-B] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1694724]
54. Kulwichit, W.; Edwards, R.H.; Davenport, E.M.; Baskar, J.F.; Godfrey, V.; Raab-Traub, N. Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc. Natl. Acad. Sci. USA; 1998; 95, pp. 11963-11968. [DOI: https://dx.doi.org/10.1073/pnas.95.20.11963]
55. Curran, J.A.; Laverty, F.S.; Campbell, D.; Macdiarmid, J.; Wilson, J.B. Epstein-Barr virus encoded latent membrane protein-1 induces epithelial cell proliferation and sensitizes transgenic mice to chemical carcinogenesis. Cancer Res.; 2001; 61, pp. 6730-6738.
56. Mainou, B.A.; Raab-Traub, N. LMP1 strain variants: Biological and molecular properties. J. Virol.; 2006; 80, pp. 6458-6468. [DOI: https://dx.doi.org/10.1128/JVI.00135-06] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16775333]
57. Lam, N.; Sugden, B. CD40 and its viral mimic, LMP1: Similar means to different ends. Cell. Signal.; 2003; 15, pp. 9-16. [DOI: https://dx.doi.org/10.1016/S0898-6568(02)00083-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12401515]
58. Caldwell, R.G.; Wilson, J.B.; Anderson, S.J.; Longnecker, R. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity; 1998; 9, pp. 405-411. [DOI: https://dx.doi.org/10.1016/S1074-7613(00)80623-8]
59. Caldwell, R.G.; Brown, R.C.; Longnecker, R. Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of EmuLMP2A transgenic mice. J. Virol.; 2000; 74, pp. 1101-1113. [DOI: https://dx.doi.org/10.1128/JVI.74.3.1101-1113.2000]
60. Thornburg, N.J.; Kulwichit, W.; Edwards, R.H.; Shair, K.H.; Bendt, K.M.; Raab-Traub, N. LMP1 signaling and activation of NF-kappaB in LMP1 transgenic mice. Oncogene; 2006; 25, pp. 288-297. [DOI: https://dx.doi.org/10.1038/sj.onc.1209023]
61. Everly, D.N., Jr.; Kusano, S.; Raab-Traub, N. Accumulation of cytoplasmic beta-catenin and nuclear glycogen synthase kinase 3beta in Epstein-Barr virus-infected cells. J. Virol.; 2004; 78, pp. 11648-11655. [DOI: https://dx.doi.org/10.1128/JVI.78.21.11648-11655.2004]
62. Li, S.S.; Yang, S.; Wang, S.; Yang, X.M.; Tang, Q.L.; Wang, S.H. Latent membrane protein 1 mediates the resistance of nasopharyngeal carcinoma cells to TRAIL-induced apoptosis by activation of the PI3K/Akt signaling pathway. Oncol. Rep.; 2011; 26, pp. 1573-1579.
63. Gires, O.; Kohlhuber, F.; Kilger, E.; Baumann, M.; Kieser, A.; Kaiser, C.; Zeidler, R.; Scheffer, B.; Ueffing, M.; Hammerschmidt, W. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J.; 1999; 18, pp. 3064-3073. [DOI: https://dx.doi.org/10.1093/emboj/18.11.3064] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10357818]
64. Ma, S.D.; Tsai, M.H.; Romero-Masters, J.C.; Ranheim, E.A.; Huebner, S.M.; Bristol, J.A.; Delecluse, H.J.; Kenney, S.C. Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate to Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential. J. Virol.; 2017; 91, e01928-16. [DOI: https://dx.doi.org/10.1128/JVI.01928-16]
65. Skalsky, R.L.; Cullen, B.R. EBV Noncoding RNAs. Curr. Top Microbiol. Immunol.; 2015; 391, pp. 181-217. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26428375]
66. Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.A.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; Freeman, C.; Hunt, S.E. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature; 2011; 476, pp. 214-219.
67. Bjornevik, K.; Cortese, M.; Healy, B.C.; Kuhle, J.; Mina, M.J.; Leng, Y.; Elledge, S.J.; Niebuhr, D.W.; Scher, A.I.; Munger, K.L. et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science; 2022; 375, pp. 296-301. [DOI: https://dx.doi.org/10.1126/science.abj8222] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35025605]
68. Thorley-Lawson, D.A. EBV Persistence–Introducing the Virus. Curr. Top Microbiol. Immunol.; 2015; 390, pp. 151-209.
69. Thacker, E.L.; Mirzaei, F.; Ascherio, A. Infectious mononucleosis and risk for multiple sclerosis: A meta-analysis. Ann. Neurol.; 2006; 59, pp. 499-503. [DOI: https://dx.doi.org/10.1002/ana.20820]
70. Wang, Z.; Kennedy, P.G.; Dupree, C.; Wang, M.; Lee, C.; Pointon, T.; Langford, T.D.; Graner, M.W.; Yu, X. Antibodies from Multiple Sclerosis Brain Identified Epstein-Barr Virus Nuclear Antigen 1 & 2 Epitopes which Are Recognized by Oligoclonal Bands. J. Neuroimmune Pharm.; 2021; 16, pp. 567-580.
71. Lanz, T.V.; Brewer, R.C.; Ho, P.P.; Moon, J.-S.; Jude, K.M.; Fernandez, D.; Fernandes, R.A.; Gomez, A.M.; Nadj, G.-S.; Bartley, C.M. et al. Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM. Nature; 2022; 603, pp. 321-327. [DOI: https://dx.doi.org/10.1038/s41586-022-04432-7]
72. Jacobs, B.M.; Giovannoni, G.; Cuzick, J.; Dobson, R. Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors. Mult. Scler.; 2020; 26, pp. 1281-1297. [DOI: https://dx.doi.org/10.1177/1352458520907901]
73. Jeon, S.M.; Shin, E.A. Exploring vitamin D metabolism and function in cancer. Exp. Mol. Med.; 2018; 50, pp. 1-14. [DOI: https://dx.doi.org/10.1038/s12276-018-0038-9]
74. Lung, M.L.; Cheung, A.K.; Ko, J.M.; Lung, H.L.; Cheng, Y.; Dai, W. The interplay of host genetic factors and Epstein-Barr virus in the development of nasopharyngeal carcinoma. Chin. J. Cancer; 2014; 33, pp. 556-568. [DOI: https://dx.doi.org/10.5732/cjc.014.10170] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25367335]
75. Delecluse, H.J.; Feederle, R.; O’Sullivan, B.; Taniere, P. Epstein–Barr virus-associated tumours: An update for the attention of the working pathologist. J. Clin. Pathol.; 2007; 60, pp. 1358-1364. [DOI: https://dx.doi.org/10.1136/jcp.2006.044586]
76. Vockerodt, M.; Yap, L.F.; Shannon-Lowe, C.; Curley, H.; Wei, W.; Vrzalikova, K.; Murray, P.G. The Epstein-Barr virus and the pathogenesis of lymphoma. J. Pathol.; 2015; 235, pp. 312-322. [DOI: https://dx.doi.org/10.1002/path.4459] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25294567]
77. Kempkes, B.; Robertson, E.S. Epstein-Barr virus latency: Current and future perspectives. Curr. Opin. Virol.; 2015; 14, pp. 138-144. [DOI: https://dx.doi.org/10.1016/j.coviro.2015.09.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26453799]
78. Wilson, J.B.; Bell, J.L.; Levine, A.J. Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J.; 1996; 15, pp. 3117-3126. [DOI: https://dx.doi.org/10.1002/j.1460-2075.1996.tb00674.x]
79. Kang, M.S.; Soni, V.; Bronson, R.; Kieff, E. Epstein-Barr virus nuclear antigen 1 does not cause lymphoma in C57BL/6J mice. J. Virol.; 2008; 82, pp. 4180-4183. [DOI: https://dx.doi.org/10.1128/JVI.02596-07]
80. Nanbo, A.; Inoue, K.; Adachi-Takasawa, K.; Takada, K. Epstein-Barr virus RNA confers resistance to interferon-alpha-induced apoptosis in Burkitt’s lymphoma. EMBO J.; 2002; 21, pp. 954-965. [DOI: https://dx.doi.org/10.1093/emboj/21.5.954] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11867523]
81. Ruf, I.K.; Lackey, K.A.; Warudkar, S.; Sample, J.T. Protection from interferon-induced apoptosis by Epstein-Barr virus small RNAs is not mediated by inhibition of PKR. J. Virol.; 2005; 79, pp. 14562-14569. [DOI: https://dx.doi.org/10.1128/JVI.79.23.14562-14569.2005]
82. Pfeffer, S.; Zavolan, M.; Grässer, F.A.; Chien, M.; Russo, J.J.; Ju, J.; John, B.; Enright, A.J.; Marks, D.; Sander, C. et al. Identification of virus-encoded microRNAs. Science; 2004; 304, pp. 734-736. [DOI: https://dx.doi.org/10.1126/science.1096781]
83. Feederle, R.; Linnstaedt, S.D.; Bannert, H.; Lips, H.; Bencun, M.; Cullen, B.R.; Delecluse, H.J. A viral microRNA cluster strongly potentiates the transforming properties of a human herpesvirus. PLoS Pathog.; 2011; 7, e1001294. [DOI: https://dx.doi.org/10.1371/journal.ppat.1001294]
84. Wang, M.; Yu, F.; Wu, W.; Wang, Y.; Ding, H.; Qian, L. Epstein-Barr virus-encoded microRNAs as regulators in host immune responses. Int. J. Biol. Sci.; 2018; 14, pp. 565-576. [DOI: https://dx.doi.org/10.7150/ijbs.24562]
85. Pang, M.F.; Lin, K.W.; Peh, S.C. The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer. Cell. Mol. Biol. Lett.; 2009; 14, pp. 222-247. [DOI: https://dx.doi.org/10.2478/s11658-008-0045-2]
86. Liu, Y.; Hu, X.; Han, C.; Wang, L.; Zhang, X.; He, X.; Lu, X. Targeting tumor suppressor genes for cancer therapy. BioEssays; 2015; 37, pp. 1277-1286. [DOI: https://dx.doi.org/10.1002/bies.201500093] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26445307]
87. Leight, E.R.; Sugden, B. EBNA-1: A protein pivotal to latent infection by Epstein-Barr virus. Rev. Med. Virol.; 2000; 10, pp. 83-100. [DOI: https://dx.doi.org/10.1002/(SICI)1099-1654(200003/04)10:2<83::AID-RMV262>3.0.CO;2-T]
88. Raab-Traub, N. Epstein-Barr virus in the pathogenesis of NPC. Semin. Cancer Biol.; 2002; 12, pp. 431-441. [DOI: https://dx.doi.org/10.1016/S1044579X0200086X] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12450729]
89. Sivachandran, N.; Dawson, C.W.; Young, L.S.; Liu, F.F.; Middeldorp, J.; Frappier, L. Contributions of the Epstein-Barr virus EBNA1 protein to gastric carcinoma. J. Virol.; 2012; 86, pp. 60-68. [DOI: https://dx.doi.org/10.1128/JVI.05623-11]
90. Sivachandran, N.; Sarkari, F.; Frappier, L. Epstein-Barr nuclear antigen 1 contributes to nasopharyngeal carcinoma through disruption of PML nuclear bodies. PLoS Pathog.; 2008; 4, e1000170. [DOI: https://dx.doi.org/10.1371/journal.ppat.1000170]
91. Holowaty, M.N.; Zeghouf, M.; Wu, H.; Tellam, J.; Athanasopoulos, V.; Greenblatt, J.; Frappier, L. Protein profiling with Epstein-Barr nuclear antigen-1 reveals an interaction with the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7. J. Biol. Chem.; 2003; 278, pp. 29987-29994. [DOI: https://dx.doi.org/10.1074/jbc.M303977200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12783858]
92. Chi, L.M.; Yu, J.S.; Chang, Y.S. Identification of protein kinase CK2 as a potent kinase of Epstein-Barr virus latent membrane protein 1. Biochem. Biophys. Res. Commun.; 2002; 294, pp. 586-591. [DOI: https://dx.doi.org/10.1016/S0006-291X(02)00515-6]
93. Cao, J.Y.; Shire, K.; Landry, C.; Gish, G.D.; Pawson, T.; Frappier, L. Identification of a novel protein interaction motif in the regulatory subunit of casein kinase 2. Mol. Cell. Biol.; 2014; 34, pp. 246-258. [DOI: https://dx.doi.org/10.1128/MCB.00968-13] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24216761]
94. Frappier, L.; O’Donnell, M. Overproduction, purification, and characterization of EBNA1, the origin binding protein of Epstein-Barr virus. J. Biol. Chem.; 1991; 266, pp. 7819-7826. [DOI: https://dx.doi.org/10.1016/S0021-9258(20)89523-4]
95. Duellman, S.J.; Thompson, K.L.; Coon, J.J.; Burgess, R.R. Phosphorylation sites of Epstein-Barr virus EBNA1 regulate its function. J. Gen. Virol.; 2009; 90, pp. 2251-2259. [DOI: https://dx.doi.org/10.1099/vir.0.012260-0] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19439552]
96. Frappier, L. Viral disruption of promyelocytic leukemia (PML) nuclear bodies by hijacking host PML regulators. Virulence; 2011; 2, pp. 58-62. [DOI: https://dx.doi.org/10.4161/viru.2.1.14610]
97. Scaglioni, P.P.; Yung, T.M.; Cai, L.F.; Erdjument-Bromage, H.; Kaufman, A.J.; Singh, B.; Teruya-Feldstein, J.; Tempst, P.; Pandolfi, P.P. A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell; 2006; 126, pp. 269-283. [DOI: https://dx.doi.org/10.1016/j.cell.2006.05.041] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16873060]
98. Scaglioni, P.P.; Yung, T.M.; Choi, S.C.; Baldini, C.; Konstantinidou, G.; Pandolfi, P.P. CK2 mediates phosphorylation and ubiquitin-mediated degradation of the PML tumor suppressor. Mol. Cell. Biochem.; 2008; 316, pp. 149-154. [DOI: https://dx.doi.org/10.1007/s11010-008-9812-7]
99. Kang, M.S.; Lee, E.K.; Soni, V.; Lewis, T.A.; Koehler, A.N.; Srinivasan, V.; Kieff, E. Roscovitine inhibits EBNA1 serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance. J. Virol.; 2011; 85, pp. 2859-2868. [DOI: https://dx.doi.org/10.1128/JVI.01628-10]
100. Shire, K.; Kapoor, P.; Jiang, K.; Hing, M.N.; Sivachandran, N.; Nguyen, T.; Frappier, L. Regulation of the EBNA1 Epstein-Barr virus protein by serine phosphorylation and arginine methylation. J. Virol.; 2006; 80, pp. 5261-5272. [DOI: https://dx.doi.org/10.1128/JVI.02682-05]
101. Grässer, F.A.; Gottel, S.; Haiss, P.; Boldyreff, B.; Issinger, O.G.; Mueller-Lantzsch, N. Phosphorylation of the Epstein-Barr virus nuclear antigen 2. Biochem. Biophys. Res. Commun.; 1992; 186, pp. 1694-1701. [DOI: https://dx.doi.org/10.1016/S0006-291X(05)81604-3]
102. Gross, H.; Hennard, C.; Masouris, I.; Cassel, C.; Barth, S.; Stober-Grässer, U.; Mamiani, A.; Moritz, B.; Ostareck, D.; Ostareck-Lederer, A. et al. Binding of the heterogeneous ribonucleoprotein K (hnRNP K) to the Epstein-Barr virus nuclear antigen 2 (EBNA2) enhances viral LMP2A expression. PLoS ONE; 2012; 7, e42106. [DOI: https://dx.doi.org/10.1371/journal.pone.0042106]
103. Shimada, K.; Kondo, K.; Yamanishi, K. Human herpesvirus 6 immediate-early 2 protein interacts with heterogeneous ribonucleoprotein K and casein kinase 2. Microbiol. Immunol.; 2004; 48, pp. 205-210. [DOI: https://dx.doi.org/10.1111/j.1348-0421.2004.tb03507.x]
104. Wadd, S.; Bryant, H.; Filhol, O.; Scott, J.E.; Hsieh, T.Y.; Everett, R.D.; Clements, J.B. The multifunctional herpes simplex virus IE63 protein interacts with heterogeneous ribonucleoprotein K and with casein kinase 2. J. Biol. Chem.; 1999; 274, pp. 28991-28998. [DOI: https://dx.doi.org/10.1074/jbc.274.41.28991] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10506147]
105. Bryant, H.E.; Matthews, D.A.; Wadd, S.; Scott, J.E.; Kean, J.; Graham, S.; Russell, W.C.; Clements, J.B. Interaction between herpes simplex virus type 1 IE63 protein and cellular protein p32. J. Virol.; 2000; 74, pp. 11322-11328. [DOI: https://dx.doi.org/10.1128/JVI.74.23.11322-11328.2000]
106. Barth, S.; Liss, M.; Voss, M.D.; Dobner, T.; Fischer, U.; Meister, G.; Grasser, F.A. Epstein-Barr virus nuclear antigen 2 binds via its methylated arginine-glycine repeat to the survival motor neuron protein. J. Virol.; 2003; 77, pp. 5008-5013. [DOI: https://dx.doi.org/10.1128/JVI.77.8.5008-5013.2003]
107. Liu, C.D.; Cheng, C.P.; Fang, J.S.; Chen, L.C.; Zhao, B.; Kieff, E.; Peng, C.W. Modulation of Epstein-Barr virus nuclear antigen 2-dependent transcription by protein arginine methyltransferase 5. Biochem. Biophys. Res. Commun.; 2013; 430, pp. 1097-1102. [DOI: https://dx.doi.org/10.1016/j.bbrc.2012.12.032] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23261437]
108. Gross, H.; Barth, S.; Palermo, R.D.; Mamiani, A.; Hennard, C.; Zimber-Strobl, U.; West, M.J.; Kremmer, E.; Grasser, F.A. Asymmetric arginine dimethylation of Epstein-Barr virus nuclear antigen 2 promotes DNA targeting. Virology; 2010; 397, pp. 299-310. [DOI: https://dx.doi.org/10.1016/j.virol.2009.11.023]
109. Kaye, K.M.; Izumi, K.M.; Kieff, E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc. Natl. Acad. Sci. USA; 1993; 90, pp. 9150-9154. [DOI: https://dx.doi.org/10.1073/pnas.90.19.9150]
110. Kieser, A.; Sterz, K.R. The Latent Membrane Protein 1 (LMP1). Curr. Top Microbiol. Immunol.; 2015; 391, pp. 119-149.
111. Baichwal, V.R.; Sugden, B. Posttranslational processing of an Epstein-Barr virus-encoded membrane protein expressed in cells transformed by Epstein-Barr virus. J. Virol.; 1987; 61, pp. 866-875. [DOI: https://dx.doi.org/10.1128/jvi.61.3.866-875.1987]
112. Diduk, S.V.; Smirnova, K.V.; Pavlish, O.A.; Gurtsevitch, V.E. Functionally significant mutations in the Epstein-Barr virus LMP1 gene and their role in activation of cell signaling pathways. Biochemistry; 2008; 73, pp. 1134-1139. [DOI: https://dx.doi.org/10.1134/S0006297908100106]
113. Mainou, B.A.; Everly, D.N., Jr.; Raab-Traub, N. Unique signaling properties of CTAR1 in LMP1-mediated transformation. J. Virol.; 2007; 81, pp. 9680-9692. [DOI: https://dx.doi.org/10.1128/JVI.01001-07]
114. Chien, K.Y.; Chang, Y.S.; Yu, J.S.; Fan, L.W.; Lee, C.W.; Chi, L.M. Identification of a new in vivo phosphorylation site in the cytoplasmic carboxyl terminus of EBV-LMP1 by tandem mass spectrometry. Biochem. Biophys. Res. Commun.; 2006; 348, pp. 47-55. [DOI: https://dx.doi.org/10.1016/j.bbrc.2006.06.188] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16875669]
115. St Denis, N.; Gabriel, M.; Turowec, J.P.; Gloor, G.B.; Li, S.S.; Gingras, A.C.; Litchfield, D.W. Systematic investigation of hierarchical phosphorylation by protein kinase CK2. J. Proteom.; 2014; 118, pp. 49-62. [DOI: https://dx.doi.org/10.1016/j.jprot.2014.10.020]
116. El-Guindy, A.S.; Miller, G. Phosphorylation of Epstein-Barr virus ZEBRA protein at its casein kinase 2 sites mediates its ability to repress activation of a viral lytic cycle late gene by Rta. J. Virol.; 2004; 78, pp. 7634-7644. [DOI: https://dx.doi.org/10.1128/JVI.78.14.7634-7644.2004]
117. El-Guindy, A.S.; Paek, S.Y.; Countryman, J.; Miller, G. Identification of constitutive phosphorylation sites on the Epstein-Barr virus ZEBRA protein. J. Biol. Chem.; 2006; 281, pp. 3085-3095. [DOI: https://dx.doi.org/10.1074/jbc.M506076200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16321978]
118. Kolman, J.L.; Taylor, N.; Marshak, D.R.; Miller, G. Serine-173 of the Epstein-Barr virus ZEBRA protein is required for DNA binding and is a target for casein kinase II phosphorylation. Proc. Natl. Acad. Sci. USA; 1993; 90, pp. 10115-10119. [DOI: https://dx.doi.org/10.1073/pnas.90.21.10115]
119. Gruffat, H.; Batisse, J.; Pich, D.; Neuhierl, B.; Manet, E.; Hammerschmidt, W.; Sergeant, A. Epstein-Barr virus mRNA export factor EB2 is essential for production of infectious virus. J. Virol.; 2002; 76, pp. 9635-9644. [DOI: https://dx.doi.org/10.1128/JVI.76.19.9635-9644.2002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12208942]
120. Cook, I.D.; Shanahan, F.; Farrell, P.J. Epstein-Barr virus SM protein. Virology; 1994; 205, pp. 217-227. [DOI: https://dx.doi.org/10.1006/viro.1994.1637] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7975218]
121. Medina-Palazon, C.; Gruffat, H.; Mure, F.; Filhol, O.; Vingtdeux-Didier, V.; Drobecq, H.; Cochet, C.; Sergeant, N.; Sergeant, A.; Manet, E. Protein kinase CK2 phosphorylation of EB2 regulates its function in the production of Epstein-Barr virus infectious viral particles. J. Virol.; 2007; 81, pp. 11850-11860. [DOI: https://dx.doi.org/10.1128/JVI.01421-07]
122. Sergeant, A.; Gruffat, H.; Manet, E. The Epstein-Barr virus (EBV) protein EB is an mRNA export factor essential for virus production. Front. Biosci.; 2008; 13, pp. 3798-3813. [DOI: https://dx.doi.org/10.2741/2969] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18508475]
123. John, L.B.; Ward, A.C. The Ikaros gene family: Transcriptional regulators of hematopoiesis and immunity. Mol. Immunol.; 2011; 48, pp. 1272-1278. [DOI: https://dx.doi.org/10.1016/j.molimm.2011.03.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21477865]
124. Dovat, E.; Song, C.; Hu, T.; Rahman, M.; Dhanyamraju, P.; Klink, M.; Bogush, D.; Soliman, M.; Kane, S.; McGrath, M. et al. Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2. Int. J. Mol. Sci.; 2021; 22, 819. [DOI: https://dx.doi.org/10.3390/ijms22020819]
125. Klink, M.; Rahman, M.; Song, C.; Dhanyamraju, P.; Ehudin, M.; Ding, Y.; Steffens, S.; Bhadauria, P.; Iyer, S.; Aliaga, C. et al. Mechanistic Basis for In Vivo Therapeutic Efficacy of CK2 Inhibitor CX-4945 in Acute Myeloid Leukemia. Cancers; 2021; 13, 1127. [DOI: https://dx.doi.org/10.3390/cancers13051127] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33807974]
126. Uckun, F.M.; Ma, H.; Zhang, J.; Ozer, Z.; Dovat, S.; Mao, C.; Ishkhanian, R.; Goodman, P.; Qazi, S. Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros. Proc. Natl. Acad. Sci. USA; 2012; 109, pp. 18072-18077. [DOI: https://dx.doi.org/10.1073/pnas.1209828109] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23071339]
127. Gomez-del, A.P.; Koipally, J.; Georgopoulos, K. Ikaros SUMOylation: Switching out of repression. Mol. Cell. Biol.; 2005; 25, pp. 2688-2697. [DOI: https://dx.doi.org/10.1128/MCB.25.7.2688-2697.2005]
128. Popescu, M.; Gurel, Z.; Ronni, T.; Song, C.; Hung, K.Y.; Payne, K.J.; Dovat, S. Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. J. Biol. Chem.; 2009; 284, pp. 13869-13880. [DOI: https://dx.doi.org/10.1074/jbc.M900209200]
129. Dovat, S.; Song, C.; Payne, K.J.; Li, Z. Ikaros, CK2 kinase, and the road to leukemia. Mol. Cell. Biochem.; 2011; 356, pp. 201-207. [DOI: https://dx.doi.org/10.1007/s11010-011-0964-5]
130. Song, C.; Li, Z.; Erbe, A.K.; Savic, A.; Dovat, S. Regulation of Ikaros function by casein kinase 2 and protein phosphatase 1. World J. Biol. Chem.; 2011; 2, pp. 126-131. [DOI: https://dx.doi.org/10.4331/wjbc.v2.i6.126]
131. Gurel, Z.; Ronni, T.; Ho, S.; Kuchar, J.; Payne, K.J.; Turk, C.W.; Dovat, S. Recruitment of ikaros to pericentromeric heterochromatin is regulated by phosphorylation. J. Biol. Chem.; 2008; 283, pp. 8291-8300. [DOI: https://dx.doi.org/10.1074/jbc.M707906200]
132. Bogush, D.; Schramm, J.; Ding, Y.; He, B.; Singh, C.; Sharma, A.; Tukaramrao, D.B.; Iyer, S.; Desai, D.; Nalesnik, G. et al. Signaling pathways and regulation of gene expression in hematopoietic cells. Adv. Biol. Regul.; 2022; 88, 100942. [DOI: https://dx.doi.org/10.1016/j.jbior.2022.100942]
133. Iempridee, T.; Reusch, J.A.; Riching, A.; Johannsen, E.C.; Dovat, S.; Kenney, S.C.; Mertz, J.E. Epstein-Barr virus utilizes Ikaros in regulating its latent-lytic switch in B cells. J. Virol.; 2014; 88, pp. 4811-4827. [DOI: https://dx.doi.org/10.1128/JVI.03706-13] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24522918]
134. Siddiqi, U.Z.; Vaidya, A.S.; Li, X.; Marcon, E.; Tsao, S.W.; Greenblatt, J.; Frappier, L. Identification of ARKL1 as a Negative Regulator of Epstein-Barr Virus Reactivation. J. Virol.; 2019; 93, e00989-19. [DOI: https://dx.doi.org/10.1128/JVI.00989-19]
135. Domingues, P.; Golebiowski, F.; Tatham, M.H.; Lopes, A.M.; Taggart, A.; Hay, R.T.; Hale, B.G. Global Reprogramming of Host SUMOylation during Influenza Virus Infection. Cell Rep.; 2015; 13, pp. 1467-1480. [DOI: https://dx.doi.org/10.1016/j.celrep.2015.10.001]
136. Vernin, C.; Thenoz, M.; Pinatel, C.; Gessain, A.; Gout, O.; Delfau-Larue, M.-H.; Nazaret, N.; Legras-Lachuer, C.; Wattel, E.; Mortreux, F. HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating OncomiRs. Cancer Res.; 2014; 74, pp. 6082-6093. [DOI: https://dx.doi.org/10.1158/0008-5472.CAN-13-3564] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25205102]
137. Chen, H.L.; Lung, M.M.; Sham, J.S.; Choy, D.T.; Griffin, B.E.; Ng, M.H. Transcription of BamHI-A region of the EBV genome in NPC tissues and B cells. Virology; 1992; 191, pp. 193-201. [DOI: https://dx.doi.org/10.1016/0042-6822(92)90181-N]
138. Hitt, M.M.; Allday, M.J.; Hara, T.; Karran, L.; Jones, M.D.; Busson, P.; Tursz, T.; Ernberg, I.; Griffin, B.E. EBV gene expression in an NPC-related tumour. EMBO J.; 1989; 8, pp. 2639-2651. [DOI: https://dx.doi.org/10.1002/j.1460-2075.1989.tb08404.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2479554]
139. Hoesel, B.; Schmid, J.A. The complexity of NF-kappaB signaling in inflammation and cancer. Mol. Cancer; 2013; 12, 86. [DOI: https://dx.doi.org/10.1186/1476-4598-12-86]
140. Dominguez, I.; Sonenshein, G.E.; Seldin, D.C. CK2 and its role in Wnt and NF-kappaB signaling: Linking development and cancer. Cell Mol. Life Sci.; 2009; 66, pp. 1850-1857. [DOI: https://dx.doi.org/10.1007/s00018-009-9153-z]
141. Verhoeven, R.J.; Tong, S.; Zhang, G.; Zong, J.; Chen, Y.; Jin, D.Y.; Chen, M.R.; Pan, J.; Chen, H. NF-kappaB Signaling Regulates Expression of Epstein-Barr Virus BART MicroRNAs and Long Noncoding RNAs in Nasopharyngeal Carcinoma. J. Virol.; 2016; 90, pp. 6475-6488. [DOI: https://dx.doi.org/10.1128/JVI.00613-16]
142. Luo, Y.; Liu, Y.; Wang, C.; Gan, R. Signaling pathways of EBV-induced oncogenesis. Cancer Cell Int.; 2021; 21, 93. [DOI: https://dx.doi.org/10.1186/s12935-021-01793-3]
143. Romieu-Mourez, R.; Landesman-Bollag, E.; Seldin, D.C.; Sonenshein, G.E. Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Res.; 2002; 62, pp. 6770-6778. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12438279]
144. Kato, T., Jr.; Delhase, M.; Hoffmann, A.; Karin, M. CK2 is a C-terminal IkappaB kinase responsible for NF-kappaB activation during the UV response. Mol. Cell; 2003; 12, pp. 829-839. [DOI: https://dx.doi.org/10.1016/S1097-2765(03)00358-7]
145. Eddy, S.F.; Guo, S.; Demicco, E.G.; Romieu-Mourez, R.; Landesman-Bollag, E.; Seldin, D.C.; Sonenshein, G.E. Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res.; 2005; 65, pp. 11375-11383. [DOI: https://dx.doi.org/10.1158/0008-5472.CAN-05-1602] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16357145]
146. Chantome, A.; Pance, A.; Gauthier, N.; Vandroux, D.; Chenu, J.; Solary, E.; Jeannin, J.F.; Reveneau, S. Casein kinase II-mediated phosphorylation of NF-kappaB p65 subunit enhances inducible nitric-oxide synthase gene transcription in vivo. J. Biol. Chem.; 2004; 279, pp. 23953-23960. [DOI: https://dx.doi.org/10.1074/jbc.M313731200]
147. Wang, D.; Westerheide, S.D.; Hanson, J.L.; Baldwin, A.S., Jr. Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J. Biol. Chem.; 2000; 275, pp. 32592-32597. [DOI: https://dx.doi.org/10.1074/jbc.M001358200]
148. Parhar, K.; Morse, J.; Salh, B. The role of protein kinase CK2 in intestinal epithelial cell inflammatory signaling. Int. J. Color. Dis.; 2007; 22, pp. 601-609. [DOI: https://dx.doi.org/10.1007/s00384-006-0193-7]
149. Yu, M.; Yeh, J.; Van, W.C. Protein kinase casein kinase 2 mediates inhibitor-kappaB kinase and aberrant nuclear factor-kappaB activation by serum factor(s) in head and neck squamous carcinoma cells. Cancer Res.; 2006; 66, pp. 6722-6731. [DOI: https://dx.doi.org/10.1158/0008-5472.CAN-05-3758]
150. Lambert, S.L.; Martinez, O.M. Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J. Immunol.; 2007; 179, pp. 8225-8234. [DOI: https://dx.doi.org/10.4049/jimmunol.179.12.8225]
151. Chen, J. Roles of the PI3K/Akt pathway in Epstein-Barr virus-induced cancers and therapeutic implications. World J. Virol.; 2012; 1, pp. 154-161. [DOI: https://dx.doi.org/10.5501/wjv.v1.i6.154] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24175221]
152. Fresno Vara, J.A.; Casado, E.; De Castro, J.; Cejas, P.; Belda-Iniesta, C.; Gonzalez-Baron, M. PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev.; 2004; 30, pp. 193-204. [DOI: https://dx.doi.org/10.1016/j.ctrv.2003.07.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15023437]
153. Torres, J.; Pulido, R. The Tumor Suppressor PTEN Is Phosphorylated by the Protein Kinase CK2 at Its C Terminus. Implications for pten stability to proteasome- mediated degradation. J. Biol. Chem.; 2001; 276, pp. 993-998. [DOI: https://dx.doi.org/10.1074/jbc.M009134200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11035045]
154. Miller, S.J.; Lou, D.Y.; Seldin, D.C.; Lane, W.S.; Neel, B.G. Direct identification of PTEN phosphorylation sites. FEBS Lett.; 2002; 528, pp. 145-153. [DOI: https://dx.doi.org/10.1016/S0014-5793(02)03274-X] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12297295]
155. Vazquez, F.; Grossman, S.R.; Takahashi, Y.; Rokas, M.V.; Nakamura, N.; Sellers, W.R. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J. Biol. Chem.; 2001; 276, pp. 48627-48630. [DOI: https://dx.doi.org/10.1074/jbc.C100556200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11707428]
156. Al-Khouri, A.M.; Ma, Y.; Togo, S.H.; Williams, S.; Mustelin, T. Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3beta. J. Biol. Chem.; 2005; 280, pp. 35195-35202. [DOI: https://dx.doi.org/10.1074/jbc.M503045200] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16107342]
157. Maccario, H.; Perera, N.M.; Davidson, L.; Downes, C.P.; Leslie, N.R. PTEN is destabilized by phosphorylation on Thr366. Biochem. J.; 2007; 405, pp. 439-444. [DOI: https://dx.doi.org/10.1042/BJ20061837]
158. Cordier, F.; Chaffotte, A.; Terrien, E.; Prehaud, C.; Theillet, F.X.; Delepierre, M.; Lafon, M.; Buc, H.; Wolff, N. Ordered phosphorylation events in two independent cascades of the PTEN C-tail revealed by NMR. J. Am. Chem. Soc.; 2012; 134, pp. 20533-20543. [DOI: https://dx.doi.org/10.1021/ja310214g]
159. Cai, L.M.; Lyu, X.M.; Luo, W.R.; Cui, X.F.; Ye, Y.F.; Yuan, C.C.; Peng, Q.X.; Wu, D.H.; Liu, T.-F.; Wang, E. et al. EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN. Oncogene; 2015; 34, pp. 2156-2166. [DOI: https://dx.doi.org/10.1038/onc.2014.341] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25347742]
160. MacPherson, M.R.; Molina, P.; Souchelnytskyi, S.; Wernstedt, C.; Martin-Perez, J.; Portillo, F.; Cano, A. Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail1 function: Potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A. Mol. Biol. Cell; 2010; 21, pp. 244-253. [DOI: https://dx.doi.org/10.1091/mbc.e09-06-0504]
161. Yang, C.F.; Yang, G.-D.; Huang, T.-J.; Li, R.; Chu, Q.-Q.; Xu, L.; Wang, M.-S.; Cai, M.-D.; Zhong, L.; Wei, H.-J. et al. EB-virus latent membrane protein 1 potentiates the stemness of nasopharyngeal carcinoma via preferential activation of PI3K/AKT pathway by a positive feedback loop. Oncogene; 2016; 35, pp. 3419-3431. [DOI: https://dx.doi.org/10.1038/onc.2015.402]
162. Ma, W.; Feng, L.; Zhang, S.; Zhang, H.; Zhang, X.; Qi, X.; Zhang, Y.; Feng, Q.; Xiang, T.; Zeng, Y. Induction of chemokine (C-C motif) ligand 5 by Epstein-Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma. Cancer Sci.; 2018; 109, pp. 1710-1722. [DOI: https://dx.doi.org/10.1111/cas.13584]
163. Wang, L.; Ren, J.; Li, G.; Moorman, J.P.; Yao, Z.Q.; Ning, S. LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required. Oncogene; 2017; 36, pp. 2265-2274. [DOI: https://dx.doi.org/10.1038/onc.2016.380]
164. Qing, L.Z.; Li, N.Y.; Li, L.; Shuang, W.; Yu, F.Y.; Yi, D.; Divakaran, J.; Xin, L.; Yan, Q.D. LMP1 antagonizes WNT/beta-catenin signalling through inhibition of WTX and promotes nasopharyngeal dysplasia but not tumourigenesis in LMP1(B95-8) transgenic mice. J. Pathol.; 2011; 223, pp. 574-583. [DOI: https://dx.doi.org/10.1002/path.2820]
165. Song, D.H.; Dominguez, I.; Mizuno, J.; Kaut, M.; Mohr, S.C.; Seldin, D.C. CK2 phosphorylation of the armadillo repeat region of b-catenin potentiates Wnt signaling. J. Biol. Chem.; 2003; 278, pp. 24018-24025. [DOI: https://dx.doi.org/10.1074/jbc.M212260200]
166. Song, D.H.; Sussman, D.J.; Seldin, D.C. Endogenous protein kinase CK2 participates in Wnt signaling in mammary epithelial cells. J. Biol. Chem.; 2000; 275, pp. 23790-23797. [DOI: https://dx.doi.org/10.1074/jbc.M909107199] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10806215]
167. Bernatik, O.; Ganji, R.S.; Dijksterhuis, J.P.; Konik, P.; Cervenka, I.; Polonio, T.; Krejci, P.; Schulte, G.; Bryja, V. Sequential activation and inactivation of Dishevelled in the Wnt/beta-catenin pathway by casein kinases. J. Biol. Chem.; 2011; 286, pp. 10396-10410. [DOI: https://dx.doi.org/10.1074/jbc.M110.169870]
168. DiMaira, G.; Salvi, M.; Arrigoni, G.; Marin, O.; Sarno, S.; Brustolon, F.; Pinna, L.A.; Ruzzene, M. Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ.; 2005; 12, pp. 668-677. [DOI: https://dx.doi.org/10.1038/sj.cdd.4401604] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15818404]
169. Ruzzene, M.; Bertacchini, J.; Toker, A.; Marmiroli, S. Cross-talk between the CK2 and AKT signaling pathways in cancer. Adv. Biol. Regul.; 2017; 64, pp. 1-8. [DOI: https://dx.doi.org/10.1016/j.jbior.2017.03.002]
170. Zheng, Y.; Qin, H.; Frank, S.J.; Deng, L.; Litchfield, D.W.; Tefferi, A.; Pardanani, A.; Lin, F.-T.; Li, J.; Sha, B. et al. A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway. Blood; 2011; 118, pp. 156-166. [DOI: https://dx.doi.org/10.1182/blood-2010-01-266320]
171. Kato, H.; Karube, K.; Yamamoto, K.; Takizawa, J.; Tsuzuki, S.; Yatabe, Y.; Kanda, T.; Katayama, M.; Ozawa, Y.; Ishitsuka, K. et al. Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways. Cancer Sci.; 2014; 105, pp. 537-544. [DOI: https://dx.doi.org/10.1111/cas.12389]
172. Zheng, H.; Li, L.L.; Hu, D.S.; Deng, X.Y.; Cao, Y. Role of Epstein-Barr virus encoded latent membrane protein 1 in the carcinogenesis of nasopharyngeal carcinoma. Cell Mol. Immunol.; 2007; 4, pp. 185-196.
173. Timofeeva, O.A.; Plisov, S.; Evseev, A.A.; Peng, S.; Jose-Kampfner, M.; Lovvorn, H.N.; Dome, J.S.; Perantoni, A.O. Serine-phosphorylated STAT1 is a prosurvival factor in Wilms’ tumor pathogenesis. Oncogene; 2006; 25, pp. 7555-7564. [DOI: https://dx.doi.org/10.1038/sj.onc.1209742]
174. Mandato, E.; Manni, S.; Zaffino, F.; Semenzato, G.; Piazza, F. Targeting CK2-driven non-oncogene addiction in B-cell tumors. Oncogene; 2016; 35, pp. 6045-6052. [DOI: https://dx.doi.org/10.1038/onc.2016.86] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27041560]
175. Manni, S.; Brancalion, A.; Mandato, E.; Tubi, L.Q.; Colpo, A.; Pizzi, M.; Cappellesso, R.; Zaffino, F.; Di Maggio, S.A.; Cabrelle, A. et al. Protein Kinase CK2 Inhibition Down Modulates the NF-kappaB and STAT3 Survival Pathways, Enhances the Cellular Proteotoxic Stress and Synergistically Boosts the Cytotoxic Effect of Bortezomib on Multiple Myeloma and Mantle Cell Lymphoma Cells. PLoS ONE; 2013; 8, e75280. [DOI: https://dx.doi.org/10.1371/journal.pone.0075280] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24086494]
176. Kalathur, M.; Toso, A.; Chen, J.; Revandkar, A.; Danzer-Baltzer, C.; Guccini, I.; Alajati, A.; Sarti, M.; Pinton, S.; Brambilla, L. et al. A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours. Nat. Commun.; 2015; 6, 7227. [DOI: https://dx.doi.org/10.1038/ncomms8227]
177. Jiang, L.; Sheikh, M.S.; Huang, Y. Decision Making by p53: Life versus Death. Mol. Cell Pharm.; 2010; 2, pp. 69-77.
178. Michael-Michalovitz, D.; Yehiely, F.; Gottlieb, E.; Oren, M. Simian virus 40 can overcome the antiproliferative effect of wild-type p53 in the absence of stable large T antigen- p53 binding. J. Virol.; 1991; 65, pp. 4160-4168. [DOI: https://dx.doi.org/10.1128/jvi.65.8.4160-4168.1991] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1649323]
179. Sato, Y.; Tsurumi, T. Genome guardian p53 and viral infections. Rev. Med. Virol.; 2012; 23, pp. 213-220. [DOI: https://dx.doi.org/10.1002/rmv.1738] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23255396]
180. Krauer, K.G.; Burgess, A.; Buck, M.; Flanagan, J.; Sculley, T.B.; Gabrielli, B. The EBNA-3 gene family proteins disrupt the G2/M checkpoint. Oncogene; 2004; 23, pp. 1342-1353. [DOI: https://dx.doi.org/10.1038/sj.onc.1207253]
181. Wade, M.; Allday, M.J. Epstein-Barr virus suppresses a G(2)/M checkpoint activated by genotoxins. Mol. Cell. Biol.; 2000; 20, pp. 1344-1360. [DOI: https://dx.doi.org/10.1128/MCB.20.4.1344-1360.2000]
182. Saridakis, V.; Sheng, Y.; Sarkari, F.; Holowaty, M.N.; Shire, K.; Nguyen, T.; Zhang, R.G.; Liao, J.; Lee, W.; Edwards, A.M. et al. Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol. Cell; 2005; 18, pp. 25-36. [DOI: https://dx.doi.org/10.1016/j.molcel.2005.02.029]
183. Liu, M.T.; Chang, Y.T.; Chen, S.C.; Chuang, Y.C.; Chen, Y.R.; Lin, C.S.; Chen, J.Y. Epstein-Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity. Oncogene; 2005; 24, pp. 2635-2646. [DOI: https://dx.doi.org/10.1038/sj.onc.1208319]
184. Li, L.; Guo, L.; Tao, Y.; Zhou, S.; Wang, Z.; Luo, W.; Hu, D.; Li, Z.; Xiao, L.; Tang, M. et al. Latent membrane protein 1 of Epstein-Barr virus regulates p53 phosphorylation through MAP kinases. Cancer Lett.; 2007; 255, pp. 219-231. [DOI: https://dx.doi.org/10.1016/j.canlet.2007.04.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17582679]
185. Li, L.; Zhou, S.; Chen, X.; Guo, L.; Li, Z.; Hu, D.; Luo, X.; Ma, X.; Tang, M.; Yi, W. et al. The activation of p53 mediated by Epstein-Barr virus latent membrane protein 1 in SV40 large T-antigen transformed cells. FEBS Lett.; 2008; 582, pp. 755-762. [DOI: https://dx.doi.org/10.1016/j.febslet.2008.01.031]
186. Husaini, R.; Ahmad, M.; Soo-Beng, K.A. Epstein-Barr virus Latent Membrane Protein LMP1 reduces p53 protein levels independent of the PI3K-Akt pathway. BMC Res. Notes; 2011; 4, 551. [DOI: https://dx.doi.org/10.1186/1756-0500-4-551] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22185663]
187. Maclaine, N.J.; Hupp, T.R. How phosphorylation controls p53. Cell Cycle; 2011; 10, pp. 916-921. [DOI: https://dx.doi.org/10.4161/cc.10.6.15076]
188. Lorenz, A.; Herrmann, C.P.E.; Issinger, O.-G.; Montenarh, M. Phosphorylation of wild-type and mutant phenotypes of p53 by an associated protein kinase. Int. J. Oncol.; 1992; 1, pp. 571-580. [DOI: https://dx.doi.org/10.3892/ijo.1.5.571]
189. Herrmann, C.P.E.; Kraiss, S.; Montenarh, M. Association of casein kinase II with immunopurified p53. Oncogene; 1991; 6, pp. 877-884.
190. Kraiss, S.; Barnekow, A.; Montenarh, M. Protein kinase activity associated with immunopurified p53 protein. Oncogene; 1990; 5, pp. 845-855. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2141685]
191. Achison, M.; Hupp, T.R. Hypoxia attenuates the p53 response to cellular damage. Oncogene; 2003; 22, pp. 3431-3440. [DOI: https://dx.doi.org/10.1038/sj.onc.1206434] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12776195]
192. Cruz, L.R.; Baladrón, I.; Rittoles, A.; Díaz, P.A.; Valenzuela, C.; Santana, R.; Vázquez, M.M.; García, A.; Chacón, D.; Thompson, D. et al. Treatment with an Anti-CK2 Synthetic Peptide Improves Clinical Response in COVID-19 Patients with Pneumonia. A Randomized and Controlled Clinical Trial. ACS Pharm. Transl. Sci.; 2021; 4, pp. 206-212. [DOI: https://dx.doi.org/10.1021/acsptsci.0c00175] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33615173]
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; Grässer, Friedrich A 2 ; Götz, Claudia 1
1 Medical Biochemistry and Molecular Biology, Saarland University, Buildings 44 and 47, 66424 Homburg, Germany
2 Institute of Virology, Saarland University, Buildings 44 and 47, 66424 Homburg, Germany