TY - JOUR
T1 - Epstein-Barr virus LMP2A interferes with global transcription factor regulation when expressed during B-lymphocyte development
AU - Portis, Toni
AU - Longnecker, Richard
PY - 2003/1
Y1 - 2003/1
N2 - Epstein-Barr virus (EBV) is associated with the development of malignant lymphomas and lymphoproliferative disorders in immunocompromised individuals. The LMP2A protein of EBV is thought to play a central role in this process by allowing the virus to persist in latently infected B lymphocytes. We have demonstrated that LMP2A, when expressed in B cells of transgenic mice, allows normal B-cell developmental checkpoints to be bypassed. To identify cellular genes targeted by LMP2A that are involved in this process, we have utilized DNA microarrays to compare gene transcription in B cells from wild-type versus LMP2A transgenic mice. In B cells from LMP2A transgenic mice, we observed decreased expression of many genes associated with normal B-cell development as well as reduced levels of the transcription factors that regulate their expression. In particular, expression of the transcription factor E2A was down-regulated in bone marrow and splenic B cells. Furthermore, E2A activity was inhibited in these cells as determined by decreased DNA binding and reduced expression of its target genes, including the transcription factors early B-cell factor and Pax-5. Expression of two E2A inhibitors, Id2 and SCL, was up-regulated in splenic B cells expressing LMP2A, suggesting a possible mechanism for E2A inhibition. These results indicate that LMP2A deregulates transcription factor expression and activity in developing B cells, and this likely allows for a bypass of normal signaling events required for proper B-cell development. The ability of LMP2A to interfere with B-cell transcription factor regulation has important implications regarding its role in EBV latency.
AB - Epstein-Barr virus (EBV) is associated with the development of malignant lymphomas and lymphoproliferative disorders in immunocompromised individuals. The LMP2A protein of EBV is thought to play a central role in this process by allowing the virus to persist in latently infected B lymphocytes. We have demonstrated that LMP2A, when expressed in B cells of transgenic mice, allows normal B-cell developmental checkpoints to be bypassed. To identify cellular genes targeted by LMP2A that are involved in this process, we have utilized DNA microarrays to compare gene transcription in B cells from wild-type versus LMP2A transgenic mice. In B cells from LMP2A transgenic mice, we observed decreased expression of many genes associated with normal B-cell development as well as reduced levels of the transcription factors that regulate their expression. In particular, expression of the transcription factor E2A was down-regulated in bone marrow and splenic B cells. Furthermore, E2A activity was inhibited in these cells as determined by decreased DNA binding and reduced expression of its target genes, including the transcription factors early B-cell factor and Pax-5. Expression of two E2A inhibitors, Id2 and SCL, was up-regulated in splenic B cells expressing LMP2A, suggesting a possible mechanism for E2A inhibition. These results indicate that LMP2A deregulates transcription factor expression and activity in developing B cells, and this likely allows for a bypass of normal signaling events required for proper B-cell development. The ability of LMP2A to interfere with B-cell transcription factor regulation has important implications regarding its role in EBV latency.
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U2 - 10.1128/JVI.77.1.105-114.2003
DO - 10.1128/JVI.77.1.105-114.2003
M3 - Article
C2 - 12477815
AN - SCOPUS:0037213918
SN - 0022-538X
VL - 77
SP - 105
EP - 114
JO - Journal of virology
JF - Journal of virology
IS - 1
ER -