The Latency-associated Nuclear Antigen of Kaposi's Sarcoma-associated Herpesvirus Modulates Cellular Gene Expression and Protects Lymphoid Cells from p16 INK4A-induced Cell Cycle Arrest

An, Feng; Compitello, Nicole; Horwitz, Edward; Sramkoski, Michael R.; Knudsen, Erik S.; Renne, Rolf

doi:10.1074/jbc.m407435200

Cited by 119 publications

(113 citation statements)

References 61 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…This phenotype is analogous to mice with constitutively active B cell CLL/lymphoma 6 (bcl-6), which also present with LPD, antigen-independent GCs, and low-frequency diffuse large B cell lymphomas at advanced age (40). LANA alone does not transform cells in culture, but ectopic expression in B cell lines rendered cells resistant to p16INK4-mediated cell-cycle arrest (25). LANA can also augment cell activation events through the ras/MAPK pathway (21), and this may provide a molecular explanation for how LANA contributes to oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…LANA binds to the p53 and pRb tumor suppressor proteins as well as glycogen synthase kinase 3b (19)(20)(21). It can function as a transcriptional activator of its own viral (22) and cellular gene promoters, which in the aggregate changes STAT-, p53-, and pRb-dependent signaling events (23)(24)(25). These molecular observations imply a role for LANA in B cell oncogenesis beyond viral maintenance, but so far have not been explored in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Fakhari

Jeong

Kanan

et al. 2006

Journal of Clinical Investigation

View full text Add to dashboard Cite

Kaposi sarcoma-associated herpesvirus (KSHV) is a human lymphotropic herpesvirus. It is implicated in B cell neoplasias such as primary effusion lymphoma and multicentric Castleman disease in AIDS patients. The KSHV latency-associated nuclear antigen (LANA) is consistently expressed in all KSHV-associated tumor cells and was shown to bind the tumor suppressor proteins p53 and pRb. To test LANA's contribution to lymphomagenesis in vivo we generated transgenic mice expressing LANA under the control of its own promoter, which is B cell specific. All of the transgenic mice developed splenic follicular hyperplasia due to an expansion of IgM + IgD + B cells and showed increased germinal center formation. We also observed lymphomas, implying that LANA can activate B cells and provide the first step toward lymphomagenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Fakhari

Jeong

Kanan

et al. 2006

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…Overexpression of Polβ was also observed in several cisplatin-resistant human tumor cell lines, including ovarian, colon, and leukemic cells (8). More recently, it has been established that up-regulation of Polβ occurs also in Burkitt's lymphoma cell lines infected by the EBV (9,10). However, the mechanisms responsible for Polβ overexpression in these EBV-related B-cell lines have never been examined.…”

Section: Introductionmentioning

confidence: 97%

Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

et al. 2009

View full text Add to dashboard Cite

The repair DNA polymerase β (Polβ), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of Polβ has been reported in many tumor types that exhibit genetic aberrations, including EBV-related B-cell lymphomas. However, the mechanisms responsible for its overexpression have never been examined. Here, we report that both expression and activity of Polβ, in EBV-immortalized B cells, are induced by several natural genetic variants of LMP1, an oncoprotein associated with the vast majority of EBV-related tumors. Conversely, we found that the expression of Polβ decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-κB (NF-κB) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-κB in the LMP1-mediated Polβ regulation. Using electrophoretic mobility shift assay experiments from several EBV-immortalized B-cell nuclear extracts, we identified an LMP1-dependent p50/c-Rel heterodimer on a proximal κB binding site (−211 to −199nt) of the Polβ promoter. This result was correlated with a specific Polβ κB transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Polβ overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-κB activation. [Cancer Res 2009; 69(12):5177-85]

show abstract

“…LANA is a multifunctional protein; it regulates a variety of cellular activities including gene transcription, DNA replication, and signaling pathways involved in cell proliferation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Kaposi Sarcoma (Ks)mentioning

confidence: 99%

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

Tan

Juillard

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: KSHV LANA binds virus DNA to mediate episome maintenance. Results: Mutating the novel LANA DNA binding domain (DBD) positive electrostatic patch engenders replication and episome persistence deficiencies. Conclusion: The LANA positive patch, possibly acting through a cell partner, is important for episome maintenance. Significance: Strategies that interfere with LANA positive patch function may allow future disruption of KSHV latency.

show abstract

The Latency-associated Nuclear Antigen of Kaposi's Sarcoma-associated Herpesvirus Modulates Cellular Gene Expression and Protects Lymphoid Cells from p16 INK4A-induced Cell Cycle Arrest

Cited by 119 publications

References 61 publications

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

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

Regulation of DNA Polymerase β by the LMP1 Oncoprotein of EBV through the Nuclear Factor-κB Pathway

The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

Contact Info

Product

Resources

About