The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma

Fakhari, Farnaz D.; Jeong, Joseph H.; Kanan, Yogita; Dittmer, Dirk P.

doi:10.1172/jci26190

Cited by 100 publications

(80 citation statements)

References 47 publications

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“…Here, LANA has been shown to regulate a large number of target genes and their promoters (1,29,35,47,75,97). Likewise, B cell-specific expression of LANA in transgenic mice induces mature B cell hyperplasia and lymphoma in a fraction of animals (21). In contrast, latent infection of B cells with KSHV has consistently failed to bring about a fully transformed phenotype (18,46,76).…”

Section: Discussionmentioning

confidence: 99%

Distinct p53, p53:LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas

Chen

Hilton

Staudt

et al. 2010

J Virol

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The role of p53 in primary effusion lymphoma (PEL) is complicated. The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) binds p53. Despite this interaction, we had found that p53 was functional in PEL, i.e., able to induce apoptosis in response to DNA damage (C. E. Petre, S. H. Sin, and D. P. Dittmer, J. Virol. 81:1912-1922, 2007), and that hdm2 was overexpressed. To further elucidate the relationship between LANA, p53, and hdm2, we purified LANA complexes from PEL by column chromatography. This confirmed that LANA bound p53. However, the LANA:p53 complexes were a minority compared to hdm2:p53 and p53:p53 complexes. The half-life of p53 was not extended, which is in contrast to the half-life of simian virus 40 T antigen-transformed cells. p53:p53, LANA:p53, and LANA:LANA complexes coexisted in PEL, and each protein was able to bind to its cognate DNA element. These data suggest that under normal conditions, p53 is inactive in PEL, thus allowing for exponential growth, but that this inactivation is driven by the relative stoichiometries of LANA, hdm2, and p53. If p53 is activated by DNA damage or nutlin-3a, the complex falls apart easily, and p53 exercises its role as guardian of the genome.Kaposi's sarcoma-associated herpesvirus (KSHV) is found in Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and tumors from patients with the plasmablastic variant of multicentric Castleman disease (MCD) (reviewed in reference 15). The latency-associated nuclear antigen (LANA) is encoded by open reading frame 73 (ORF 73) of the viral genome. It is expressed in every KSHV-infected cell during the latent as well as lytic phase of the viral life cycle. LANA is required for replication and maintenance of the viral DNA during latent infection (2, 13). Experimental abrogation of LANA expression through small interfering RNA (siRNA) or genomic knockout leads to loss of KSHV from latently infected cells, genetically demonstrating that LANA is necessary for maintenance of latency (28,103). LANA is a large protein composed of 1,162 amino acids (KSHV M type, reference sequence NC_003409). It has many known biochemical activities, and many more have yet to be determined. One way to think about LANA is as a nuclear scaffolding protein for viral DNA replication and transcription, analogous to the large T antigen of the polyomaviruses.We hypothesized that there exist multiple biochemically distinct LANA complexes in KSHV-infected PEL, as both LANA and its many potential interaction partners are present at physiological molar ratios to each other. Biochemical analysis of purified native complexes in PEL allowed us to establish that not all of LANA was part of a LANA:p53 complex and that not all of p53 was bound to LANA.The C terminus of the LANA protein has sequence-specific DNA binding activity. LANA can bind to a 20-bp repeated cis element in the terminal repeats (TRs) of the viral genome (3,26,27,45,50,78,85,101). We previously identified a similar cis element that was present as a single c...

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Section: Discussionmentioning

confidence: 99%

Distinct p53, p53:LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas

Chen

Hilton

Staudt

et al. 2010

J Virol

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“…For example, expression of LANA inhibits p53-mediated apoptosis and also overcomes senescence in Saos2 cells induced by expression of retinoblastoma protein 1 (RB1) (21,60,63,66,71). LANA also induces B-cell hyperplasia and lymphomas in transgenic mice, and LANA prolongs the life span of primary endothelial cells (19,78). In addition, LANA modulates the Wnt signaling pathway by binding to and altering the activity of glycogen synthase kinase-3ß, resulting in increased levels of ß-catenin (22)(23)(24)48).…”

mentioning

confidence: 99%

Role of Kaposi's Sarcoma-Associated Herpesvirus C-Terminal LANA Chromosome Binding in Episome Persistence

Kelley-Clarke

Leon-Vazquez

Slain

et al. 2009

J Virol

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“…Transgenic mice expressing KSHV LANA were previously described (21). CD19 knockout mice [C.129P2-Cd19…”

Section: Methodsmentioning

confidence: 99%

“…ϩ mature B cells (21). In these mice LANA is under the control of its own viral promoter, which is B cell specific (28).…”

mentioning

confidence: 99%

The Viral Latency-Associated Nuclear Antigen Augments the B-Cell Response to AntigenIn Vivo

Sin

Fakhari

Dittmer

2010

J Virol

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Gammaherpesviruses, including Kaposi sarcoma-associated herpesvirus (KSHV), establish latency in B cells. We hypothesized that the KSHV latency-associated nuclear antigen (LANA/orf73) provides a selective advantage to infected B cells by driving proliferation in response to antigen. To test this, we used LANA B-cell transgenic mice. Eight days after immunization with antigen without adjuvant, LANA mice had significantly more activated germinal center (GC) B cells (CD19 ؉ PNA ؉ CD71 ؉ ) than controls. This was dependent upon B-cell receptor since LANA did not restore the GC defect of CD19 knockout mice. However, LANA was able to restore the marginal zone defect in CD19 knockout mice.

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The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma

Cited by 100 publications

References 47 publications

Distinct p53, p53:LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas

Distinct p53, p53:LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas

Role of Kaposi's Sarcoma-Associated Herpesvirus C-Terminal LANA Chromosome Binding in Episome Persistence

The Viral Latency-Associated Nuclear Antigen Augments the B-Cell Response to AntigenIn Vivo

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