2022
DOI: 10.3390/cancers14030611
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The Central Role of the Ubiquitin–Proteasome System in EBV-Mediated Oncogenesis

Abstract: Deregulation of the ubiquitin–proteasome system (UPS) plays a critical role in the development of numerous human cancers. Epstein–Barr virus (EBV), the first known human tumor virus, has evolved distinct molecular mechanisms to manipulate the ubiquitin–proteasome system, facilitate its successful infection, and drive opportunistic cancers. The interactions of EBV antigens with the ubiquitin–proteasome system can lead to oncogenesis through the targeting of cellular factors involved in proliferation. Recent stu… Show more

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Cited by 9 publications
(9 citation statements)
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“…The modulation of LMP1 by EBV miRs likely plays a crucial role in enhancing the aggressiveness of EBV-associated cancers by regulating signaling pathways linked to cell survival and proliferation and tumor progression phenomena [ 32 ]. Overall, EBV can exploit the UPS pathway by inhibiting proteasomal degradation to avoid the loss of critical viral proteins or inducing the degradation of unwanted cellular proteins [ 33 ]. For instance, the UBS may be inhibited in an EBNA1-mediated way, aiding immune evasion of EBV-infected cells by impeding the generation of antigenic peptides presented to T cytotoxic cells via MHC-I molecules [ 34 ].…”
Section: Discussionmentioning
confidence: 99%
“…The modulation of LMP1 by EBV miRs likely plays a crucial role in enhancing the aggressiveness of EBV-associated cancers by regulating signaling pathways linked to cell survival and proliferation and tumor progression phenomena [ 32 ]. Overall, EBV can exploit the UPS pathway by inhibiting proteasomal degradation to avoid the loss of critical viral proteins or inducing the degradation of unwanted cellular proteins [ 33 ]. For instance, the UBS may be inhibited in an EBNA1-mediated way, aiding immune evasion of EBV-infected cells by impeding the generation of antigenic peptides presented to T cytotoxic cells via MHC-I molecules [ 34 ].…”
Section: Discussionmentioning
confidence: 99%
“…For EBV+ lymphoid malignancies including EBV+ PTLD, the survival and replication of the EBV in the transformed B cell is dependent on the interaction of EBV viral proteins with the ubiquitin-proteosome system to promote immune evasion, cell cycle disruption and inhibition of apoptosis, processes that can potentially be reversed by PIs. 85,86 Bortezomib can restore the lytic cycle of EBV and by inhibition of NF-κB (which is activated by LMP1) can restore sensitivity to proapoptotic inducers. 80 A clinical phase 2 trial of bortezomib plus rituximab in patients with PTLD was terminated due to lack of funding (NCT00869323).…”
Section: Proteosome Inhibitorsmentioning
confidence: 99%
“…Proteosome inhibitors (PIs) could exhibit anticancer activity by inhibiting cell growth and promoting cell death via various mechanisms with inhibition of the NF‐κB pathway being a key mechanism. For EBV+ lymphoid malignancies including EBV+ PTLD, the survival and replication of the EBV in the transformed B cell is dependent on the interaction of EBV viral proteins with the ubiquitin‐proteosome system to promote immune evasion, cell cycle disruption and inhibition of apoptosis, processes that can potentially be reversed by PIs 85,86 . Bortezomib can restore the lytic cycle of EBV and by inhibition of NF‐κB (which is activated by LMP1) can restore sensitivity to proapoptotic inducers 80 .…”
Section: Introductionmentioning
confidence: 99%
“…All EBV latently infected cells also display abundant expressions of noncoding EBER RNAs and transcripts from the BamHI-A region of the viral genome known as BART transcripts that are precursors to BART miRNA [ 13 , 16 ]. Regardless of modality, successful latent infection persists due to the ability of latent proteins to modify B cell receptor (BCR) signaling and evade the immune response via manipulation of host cellular pathways such as the UPS [ 8 , 17 ]. Of the latently expressed genes, LMP1, LMP2A, EBNA1, and EBNA3C have a demonstrated ability to hijack various E3 ubiquitin ligases to modulate BCR signaling and promote latency ( Table 1 ) [ 17 ].…”
Section: Gammaherpesvirusesmentioning
confidence: 99%
“…Regardless of modality, successful latent infection persists due to the ability of latent proteins to modify B cell receptor (BCR) signaling and evade the immune response via manipulation of host cellular pathways such as the UPS [ 8 , 17 ]. Of the latently expressed genes, LMP1, LMP2A, EBNA1, and EBNA3C have a demonstrated ability to hijack various E3 ubiquitin ligases to modulate BCR signaling and promote latency ( Table 1 ) [ 17 ]. Like all herpesviruses, the alternate life stage of EBV is lytic replication.…”
Section: Gammaherpesvirusesmentioning
confidence: 99%