Oncogenic Properties of the EBV ZEBRA Protein
Abstract
1. Introduction
1.1. EBV Life Cycle
1.1.1. Latency
1.1.2. Lytic Cycle
1.2. EBV-Related Oncogenesis
2. ZEBRA Structure and Functions
2.1. ZEBRA Domain Organisation
2.2. Posttranslational Modifications of ZEBRA
2.3. ZEBRA Functioning in Host Cells
2.3.1. Transcriptional Regulation
2.3.2. Binding to the Replication Origin in EBV Lytic Replication
2.3.3. Interaction with Other Cellular Proteins
3. EBV-Related Diseases and Oncogenic Properties of ZEBRA
3.1. ZEBRA Implication in EBV-Related Malignancies
3.2. ZEBRA Oncogenic Properties
3.2.1. Genome Instability
3.2.2. Tumor-Promoting Inflammation
3.2.3. Immune Evasion
3.2.4. Cell Proliferation and Growth
3.2.5. Resistance to Cell Death
3.2.6. Other Oncogenic Effects
4. ZEBRA in Diagnosis and Therapy
5. Conclusions and Remaining Questions
Supplementary Materials
Funding
Conflicts of Interest
Abbreviations
AID | activation-induced deaminase |
AIDS | acute immunodeficiency syndrome |
AITL | angioimmunoblastic T cell lymphoma |
AP-1 | activator protein 1 |
ATM | ataxia telangiectasia mutated |
BALF | BamHI-A fragment leftward open reading frame |
BARF | BamHI-A fragment rightward open reading frame |
BART | BamHI-A fragment rightward transcript |
BGLF | BamHI-G fragment leftward open reading frame |
BHRF | BamHI-H fragment rightward open reading frame |
BILF | BamHI-I fragment leftward open reading frame |
BL | Burkitt’s lymphoma |
BLLF | BamHI-L fragment leftward open reading frame |
BMRF | BamHI-M fragment rightward open reading frame |
BNLF | BamHI-N fragment leftward open reading frame |
bZIP | basic leucine zipper |
BRLF | BamHI-R fragment leftward open reading frame |
BZLF | BamH1-Z fragment leftward open reading frame |
CNS | central nervous system |
CPB | CREB binding protein |
CPD | cell penetration domain |
CR | complement receptors |
DBD | DNA binding domain of ZEBRA |
DD | dimerization domain of ZEBRA |
DLBCL | diffuse large B cell lymphoma |
EBER | EBV-encoded small RNA |
eBL | endemic Burkitt’s lymphoma |
EBNA | EBV nuclear antigen |
EBV | Epstein-Barr Virus |
ECS | Elongin B/C-Cul2/5-SOCS-box protein |
GC | germinal center |
GI | genome instability |
HDAC | histone deacetylases |
hIL | human interleukin |
HIV | human immunodeficiency virus |
HL | Hodgkin lymphoma |
HLA | human leukocyte antigen |
IARC | international agency for research on cancer |
IE | immediate early |
IFN | interferon |
IGH | immunoglobulin heavy chain |
IL | interleukin |
LCL | lymphoblastoid cell lines |
LMP | latent membrane protein |
MHC | major histocompatibility complex |
MMP | matrix metalloproteinase |
MYC | myelocytoma |
NF-κB | nuclear factor kappa B |
NFAT | nuclear factor activated T cells |
NHL | non-hodgkin lymphoma |
NK | natural killers |
NLS | nuclear localization sequence |
NOS | DLBCL not otherwise specified |
NPC | nasopharyngeal carcinoma |
PAL | pyothorax associated lymphoma |
PBL | peripheral blood lymphocytes |
PEL | primary effusion lymphoma |
PTLD | post-transplant lymphoproliferative disorders |
ROS | reactive oxygen species |
SCID | severe combined immunodeficiency |
SUMO-1 | small ubiquitin-related modifier 1 |
TAD | transactivation domain of ZEBRA |
TAP | transporter associated with antigen processing |
TGF-β | tumor growth factor β |
TNF | tumor necrosis factor |
TNFR | tumor necrosis factor receptor |
VEGF | vascular endothelial growth factor |
vIL | viral interleukin |
WT | wild type |
ZRE | ZEBRA response elements |
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Diseases | % EBV Association | Latency Type a |
---|---|---|
B-cells malignancies | ||
Burkitt Lymphoma | ||
• Endemic BL | ˃95% | I |
• Sporadic BL | 20–80% | I |
Classical Hodgkin Lymphoma | 20–90% | II |
Diffuse Large B Cells Lymphoma (DLBCL) | ||
• EBV+ DLBCL Not Otherwise Specified (NOS) | 100% | III |
• Pyothorax associated Lymphoma (PAL) | 100% | III |
T/NK cells malignancies | ||
Extranodal NK/T-cell lymphoma, nasal type | ˃95% | I/II |
Virus-associated hemophagocytic syndrome T-cell lymphoma | 100% | I/II |
Angioimmunoblastic T-cell Lymphoma (AITL) b | ˃80% | I/II |
Hepatosplenic T-cell lymphoma | ||
Non-hepatosplenic γδ T-cell lymphomas | ||
Enteropathy-type T-cell Lymphoma | ||
Epithelial malignancies | ||
Undifferentiated Nasopharyngeal carcinoma | 100% | II |
Gastric carcinoma | 10% | II |
Lymphoepithelioma-like carcinoma (salivary gland, tonsils, larynx, thymus, lungs, skin, uterus cervix, bladder, stomach) | ||
Breast carcinoma | ||
Hepatocellular carcinoma | ||
Mesenchymal malignancies | ||
Follicular dendritic cell sarcoma |
Diseases | % EBV Association | Latency Type a |
---|---|---|
Acquired Immunodeficiency | ||
AIDS-associated B cell lymphomas | ||
• BL | 30–50% | I |
• Hodgkin Lymphoma | 100% | II |
• DLBCL | ||
○ Immunoblastic | 70–100% | II/III |
○ Non Immunoblastic | 10–30% | II/III |
○ Central Nervous System lymphoma (CNS) | ˃95% | II/III |
○ Primary Effusion Lymphoma (PEL) | 70–90% | I |
○ Plasmablastic lymphoma | 60–75% | I |
Post-transplantation lymphoproliferative disorder | ˃90% | III |
Lymphomatoid granulomatosis | ||
Methotrexate-associated B cell lymphoma | ||
Leiomyosarcoma | ||
Congenital immunodeficiency | ||
Severe combined immunodeficiency–associated B cell lymphoma | ||
Wiskott-Aldrich syndrome–associated B cell lymphomas | ||
X-linked lymphoproliferative disorder–associated B cell lymphomas |
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Germini, D.; Sall, F.B.; Shmakova, A.; Wiels, J.; Dokudovskaya, S.; Drouet, E.; Vassetzky, Y. Oncogenic Properties of the EBV ZEBRA Protein. Cancers 2020, 12, 1479. https://doi.org/10.3390/cancers12061479
Germini D, Sall FB, Shmakova A, Wiels J, Dokudovskaya S, Drouet E, Vassetzky Y. Oncogenic Properties of the EBV ZEBRA Protein. Cancers. 2020; 12(6):1479. https://doi.org/10.3390/cancers12061479
Chicago/Turabian StyleGermini, Diego, Fatimata Bintou Sall, Anna Shmakova, Joëlle Wiels, Svetlana Dokudovskaya, Emmanuel Drouet, and Yegor Vassetzky. 2020. "Oncogenic Properties of the EBV ZEBRA Protein" Cancers 12, no. 6: 1479. https://doi.org/10.3390/cancers12061479
APA StyleGermini, D., Sall, F. B., Shmakova, A., Wiels, J., Dokudovskaya, S., Drouet, E., & Vassetzky, Y. (2020). Oncogenic Properties of the EBV ZEBRA Protein. Cancers, 12(6), 1479. https://doi.org/10.3390/cancers12061479