Role of Defective Oct-2 and OCA-B Expression in Immunoglobulin Production and Kaposi's Sarcoma-Associated Herpesvirus Lytic Reactivation in Primary Effusion Lymphoma

Bartolo, Daniel L. Di; Hyjek, Elizabeth; Keller, Shannon A.; Guasparri, Ilaria; Deng, Hongyu; Sun, Ren; Chadburn, Amy; Knowles, Daniel M.; Cesarman, Ethel

doi:10.1128/jvi.02196-08

Cited by 13 publications

(16 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, since both EBV and KSHV establish viral latency in B cells, this leads to the question of whether Oct-2 has an effect similar to that of Oct-1 in regulating lytic viral reactivation. In the case of KSHV, a recent report showed that Oct-2 functions as a negative regulator of viral reactivation by competing with Oct-1 for viral promoter octamer binding sites and thereby helps to promote viral latency in B cells (20). We have likewise found that Oct-2 inhibits, rather than promotes, lytic EBV reactivation (A. R. Robinson, S. Kwek, and S. C. Kenney, unpublished data).…”

Section: Discussionmentioning

confidence: 65%

Cellular Transcription Factor Oct-1 Interacts with the Epstein-Barr Virus BRLF1 Protein To Promote Disruption of Viral Latency

Robinson

Kwek

Hagemeier

et al. 2011

J Virol

View full text Add to dashboard Cite

The Epstein-Barr virus (EBV) latent-to-lytic switch is an essential part of the viral life cycle, but the cellular factors that promote viral reactivation are not well defined. In this report, we demonstrate that the cellular transcription factor Oct-1 cooperates with the EBV immediate-early protein BRLF1 (R, Rta) to induce lytic viral reactivation. We show that cotransfected Oct-1 enhances the ability of BRLF1 to activate lytic gene expression in 293 cells stably infected with a BRLF1-defective EBV mutant (BRLF1-stop) and that Oct-1 increases BRLF1-mediated activation of lytic EBV promoters in reporter gene assays. We find that Oct-1 interacts directly with BRLF1 in vitro and that a mutant BRLF1 protein (the M140A mutant) attenuated for the ability to interact with Oct-1 in vitro is also resistant to Oct-1-mediated transcriptional enhancement in 293 BRLF1-stop cells. Furthermore, we show that cotransfected Oct-1 augments BRLF1 binding to a variety of lytic EBV promoters in chromatin immunoprecipitation (ChIP) assays (including the BZLF1, BMRF1, and SM promoters) and that BRLF1 tethers Oct-1 to lytic EBV promoters. In addition, we demonstrate that an Oct-1 mutant defective in DNA binding (the S335D mutant) still retains the ability to enhance BRLF1 transcriptional effects. Finally, we show that knockdown of endogenous Oct-1 expression reduces the level of constitutive lytic EBV gene expression in both EBV-positive B-cell and EBV-positive epithelial cell lines. These results suggest that Oct-1 acts as a positive regulator of EBV lytic gene expression and that this effect is at least partially mediated through its interaction with the viral protein BRLF1. Epstein-Barr virus (EBV), or human herpesvirus 4 (HHV4), is a double-stranded DNA gammaherpesvirus which infects approximately 90% of the world's population (66). It causes a relatively mild primary disease if acquired early in life and infectious mononucleosis if acquired after adolescence. EBV is also associated with several B-cell and epithelial cell cancers, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma (NPC), and gastric carcinoma (66, 101).EBV infection persists for the life of the host as a chronic asymptomatic infection by establishing latency in memory B cells (77). However, to be transmitted from host to host, and from cell to cell, the virus periodically reactivates from latency and converts to the lytic form of replication (66). Reactivation of lytic EBV infection in host cells is controlled at the level of the BZLF1 (Z, Zta, ZEBRA, EB1) and BRLF1 (R, Rta) viral promoters, as well as the activity of the BZLF1 and BRLF1 gene products (24,42,95). The BZLF1 and BRLF1 genes encode transcription factors that cooperatively turn on the expression of the early lytic viral genes involved in lytic viral replication (2,9,16,17,23,24,26,29,31,41,50,62,68), and the overexpression of either BZLF1 or BRLF1 is sufficient to induce lytic gene expression in many latently infected cell lines (13-15, 63, 83, 96). Since the combination of both BZL...

show abstract

Section: Discussionmentioning

confidence: 65%

Cellular Transcription Factor Oct-1 Interacts with the Epstein-Barr Virus BRLF1 Protein To Promote Disruption of Viral Latency

Robinson

Kwek

Hagemeier

et al. 2011

J Virol

View full text Add to dashboard Cite

show abstract

“…Down-regulation of Oct2 and its coactivator Bob-1 has been linked to abnormal Ig expression in Hodgkin and Reed-Sternberg (HRS) cells in Hodgkin disease (166, 167) and in primary effusion lymphoma (PEL) (168). Oct2 and Bob-1 are useful markers for the differential diagnosis of classic Hodgkin lymphoma (169).…”

Section: Pathophysiological Roles Of Oct Proteinsmentioning

confidence: 99%

“…Oct2 competes with Oct1, which enhances ORF50 transactivation. Thus, down-regulation of Oct2 may promote viral reactivation of HHV-8 (168). …”

Section: Pathophysiological Roles Of Oct Proteinsmentioning

confidence: 99%

Octamer-binding transcription factors: genomics and functions

Zhao¹

2013

Front Biosci

View full text Add to dashboard Cite

The Octamer-binding proteins (Oct) are a group of highly conserved transcription factors that specifically bind to the octamer motif (ATGCAAAT) and closely related sequences that are found in promoters and enhancers of a wide variety of both ubiquitously expressed and cell type-specific genes. Oct factors belong to the larger family of POU domain factors that are characterized by the presence of a highly conserved bipartite DNA binding domain, consisting of an amino-terminal specific subdomain (POUS) and a carboxyl-terminal homeo-subdomain (POUH). Eleven Oct proteins have been named (Oct1-11), and currently, eight genes encoding Oct proteins (Oct1, Oct2, Oct3/4, Oct6, Oct7, Oct8, Oct9, and Oct11) have been cloned and characterized. Oct1 and Oct2 are widely expressed in adult tissues, while other Oct proteins are much more restricted in their expression patterns. Oct proteins are implicated in crucial and versatile biological events, such as embryogenesis, neurogenesis, immunity, and body glucose and amino acid metabolism. The aberrant expression and null function of Oct proteins have also been linked to various diseases, including deafness, diabetes and cancer. In this review, I will report both the genomic structure and major functions of individual Oct proteins in physiological and pathological processes.

show abstract

“…Several cellular factors, such as XBP-1, Ras, Ets-1, PARP-1, hKFC, CBP, the SWI/SNF chromatin remodeling complex, the TRAP/Mediator complex, RBP-J, human Notch intracellular domain, and HMGB1, have been shown to promote KSHV reactivation and/or lytic gene expression (11,31,32,44,71,72,75,76), suggesting a close link between many cellular processes and KSHV reactivation. Other cellular factors, such as Oct-2, KAP-1, and Hey1, were found to inhibit KSHV reactivation and/or lytic gene expression (12,19,25). However, the regulation of KSHV reactivation by cellular signals is still not fully understood.…”

mentioning

confidence: 99%

Oxidative Stress Induces Reactivation of Kaposi's Sarcoma-Associated Herpesvirus and Death of Primary Effusion Lymphoma Cells

Feng

Sun

2011

J Virol

Self Cite

View full text Add to dashboard Cite

Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) cells are predominantly infected with latent Kaposi's sarcoma-associated herpesvirus (KSHV), presenting a barrier to the destruction of tumor cells. Latent KSHV can be reactivated to undergo lytic replication. Here we report that in PEL cells, oxidative stress induced by upregulated reactive oxygen species (ROS) can lead to KSHV reactivation or cell death. ROS are upregulated by NF-B inhibition and are required for subsequent KSHV reactivation. Disruption of the intracellular redox balance through depletion of the antioxidant glutathione or inhibition of the antioxidant enzyme catalase also induces KSHV reactivation, suggesting that hydrogen peroxide induces reactivation. In addition, p38 signaling is required for KSHV reactivation induced by ROS. Furthermore, treatment of PEL cells with a higher concentration of the NF-B inhibitor than that used for inducing KSHV reactivation further upregulates ROS and induces massive cell death. ROS, but not p38 signaling, are required for PEL cell death induced by NF-B inhibition as well as by glutathione depletion. Importantly, anticancer drugs, such as cisplatin and arsenic trioxide, also induce KSHV reactivation and PEL cell death in a ROS-dependent manner. Our study thus establishes a critical role for ROS and oxidative stress in the regulation of KSHV reactivation and PEL cell death. Disrupting the cellular redox balance may be a potential strategy for treating KSHVassociated lymphoma.Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic human DNA virus belonging to the gammaherpesvirus family. KSHV causes Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and a plasmablastic subtype of multicentric Castleman disease (MCD) (8,13,22). KSHV has two phases in its life cycle, i.e., latency and lytic replication. During lytic replication, most of the viral genes are expressed and new virions are produced to facilitate virus propagation and transmission. In contrast, only a few viral genes are expressed during latency (20, 57), enabling KSHV to evade immune surveillance and promoting virus persistence (3). KSHV persists in its latent form in the majority of KS and PEL tumors (21,53,77). Thus, latency presents a barrier to the elimination of KSHV and the treatment of KSHV-associated tumors.Therapeutic induction of virus reactivation provides an opportunity to target and eliminate KSHV-associated tumor cells (1,29,70). A key prerequisite to the success of this approach is to understand how cellular signals regulate KSHV reactivation in order for us to target specific cellular pathways to achieve efficient virus reactivation in tumor cells. KSHV replication and transcription activator (RTA) is the key viral regulator of virus reactivation (49, 61). RTA can activate the transcription of its target genes through direct binding to RTAresponsive elements (RRE) (59, 60) or by using cellular coregulators, such as CSL/RBP-J (44, 51), Oct-1 (55), C/EBP␣ (68), and AP1 (67). KSHV also encodes negative regulators of vi...

show abstract

Role of Defective Oct-2 and OCA-B Expression in Immunoglobulin Production and Kaposi's Sarcoma-Associated Herpesvirus Lytic Reactivation in Primary Effusion Lymphoma

Cited by 13 publications

References 75 publications

Cellular Transcription Factor Oct-1 Interacts with the Epstein-Barr Virus BRLF1 Protein To Promote Disruption of Viral Latency

Cellular Transcription Factor Oct-1 Interacts with the Epstein-Barr Virus BRLF1 Protein To Promote Disruption of Viral Latency

Octamer-binding transcription factors: genomics and functions

Oxidative Stress Induces Reactivation of Kaposi's Sarcoma-Associated Herpesvirus and Death of Primary Effusion Lymphoma Cells

Contact Info

Product

Resources

About