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EBV-encoded LMP1 upregulates Igκ 3'enhancer activity and Igκ expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling.
PLoS One. 2012; 7(3):e32624.Plos

Abstract

Accumulating evidence indicates that epithelial cancer cells, including nasopharyngeal carcinoma (NPC) cells, express immunoglobulins (Igs). We previously found that the expression of the kappa light chain protein in NPC cells can be upregulated by the EBV-encoded latent membrane protein 1 (LMP1). In the present study, we used NPC cell lines as models and found that LMP1-augmented kappa production corresponds with elevations in ERKs phosphorylation. PD98059 attenuates LMP1-induced ERKs phosphorylation resulting in decreased expression of the kappa light chain. ERK-specific small interfering RNA blunts LMP1-induced kappa light chain gene expression. Luciferase reporter assays demonstrate that immunoglobulin κ 3' enhancer (3'E(κ)) is active in Igκ-expressing NPC cells and LMP1 upregulates the activity of 3'E(κ) in NPC cells. Moreover, mutation analysis of the PU binding site in 3'E(κ) and inhibition of the MEK/ERKs pathway by PD98059 indicate that the PU site is functional and LMP1-enhanced 3'E(κ) activity is partly regulated by this site. PD98059 treatment also leads to a concentration-dependent inhibition of LMP1-induced Ets-1 expression and phosphorylation, which corresponds with a dose-dependent attenuation of LMP1-induced ERK phosphorylation and kappa light chain expression. Suppression of endogenous Ets-1 by small interfering RNA is accompanied by a decrease of Ig kappa light chain expression. Gel shift assays using nuclear extracts of NPC cells indicate that the transcription factor Ets-1 is recruited by LMP1 to the PU motif within 3'E(κ)in vitro. ChIP assays further demonstrate Ets-1 binding to the PU motif of 3'E(κ) in cells. These results suggest that LMP1 upregulates 3'E(κ) activity and kappa gene expression by activating the Ets-1 transcription factor through the ERKs signaling pathway. Our studies provide evidence for a novel regulatory mechanism of kappa expression, by which virus-encoded proteins activate the kappa 3' enhancer through activating transcription factors in non-B epithelial cancer cells.

Authors+Show Affiliations

Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22396784

Citation

Liu, Haidan, et al. "EBV-encoded LMP1 Upregulates Igκ 3'enhancer Activity and Igκ Expression in Nasopharyngeal Cancer Cells By Activating the Ets-1 Through ERKs Signaling." PloS One, vol. 7, no. 3, 2012, pp. e32624.
Liu H, Duan Z, Zheng H, et al. EBV-encoded LMP1 upregulates Igκ 3'enhancer activity and Igκ expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling. PLoS One. 2012;7(3):e32624.
Liu, H., Duan, Z., Zheng, H., Hu, D., Li, M., Tao, Y., Bode, A. M., Dong, Z., & Cao, Y. (2012). EBV-encoded LMP1 upregulates Igκ 3'enhancer activity and Igκ expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling. PloS One, 7(3), e32624. https://doi.org/10.1371/journal.pone.0032624
Liu H, et al. EBV-encoded LMP1 Upregulates Igκ 3'enhancer Activity and Igκ Expression in Nasopharyngeal Cancer Cells By Activating the Ets-1 Through ERKs Signaling. PLoS One. 2012;7(3):e32624. PubMed PMID: 22396784.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - EBV-encoded LMP1 upregulates Igκ 3'enhancer activity and Igκ expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling. AU - Liu,Haidan, AU - Duan,Zhi, AU - Zheng,Hui, AU - Hu,Duosha, AU - Li,Ming, AU - Tao,Yongguang, AU - Bode,Ann M, AU - Dong,Zigang, AU - Cao,Ya, Y1 - 2012/03/01/ PY - 2011/07/27/received PY - 2012/02/01/accepted PY - 2012/3/8/entrez PY - 2012/3/8/pubmed PY - 2012/7/24/medline SP - e32624 EP - e32624 JF - PloS one JO - PLoS One VL - 7 IS - 3 N2 - Accumulating evidence indicates that epithelial cancer cells, including nasopharyngeal carcinoma (NPC) cells, express immunoglobulins (Igs). We previously found that the expression of the kappa light chain protein in NPC cells can be upregulated by the EBV-encoded latent membrane protein 1 (LMP1). In the present study, we used NPC cell lines as models and found that LMP1-augmented kappa production corresponds with elevations in ERKs phosphorylation. PD98059 attenuates LMP1-induced ERKs phosphorylation resulting in decreased expression of the kappa light chain. ERK-specific small interfering RNA blunts LMP1-induced kappa light chain gene expression. Luciferase reporter assays demonstrate that immunoglobulin κ 3' enhancer (3'E(κ)) is active in Igκ-expressing NPC cells and LMP1 upregulates the activity of 3'E(κ) in NPC cells. Moreover, mutation analysis of the PU binding site in 3'E(κ) and inhibition of the MEK/ERKs pathway by PD98059 indicate that the PU site is functional and LMP1-enhanced 3'E(κ) activity is partly regulated by this site. PD98059 treatment also leads to a concentration-dependent inhibition of LMP1-induced Ets-1 expression and phosphorylation, which corresponds with a dose-dependent attenuation of LMP1-induced ERK phosphorylation and kappa light chain expression. Suppression of endogenous Ets-1 by small interfering RNA is accompanied by a decrease of Ig kappa light chain expression. Gel shift assays using nuclear extracts of NPC cells indicate that the transcription factor Ets-1 is recruited by LMP1 to the PU motif within 3'E(κ)in vitro. ChIP assays further demonstrate Ets-1 binding to the PU motif of 3'E(κ) in cells. These results suggest that LMP1 upregulates 3'E(κ) activity and kappa gene expression by activating the Ets-1 transcription factor through the ERKs signaling pathway. Our studies provide evidence for a novel regulatory mechanism of kappa expression, by which virus-encoded proteins activate the kappa 3' enhancer through activating transcription factors in non-B epithelial cancer cells. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22396784/EBV_encoded_LMP1_upregulates_Igκ_3'enhancer_activity_and_Igκ_expression_in_nasopharyngeal_cancer_cells_by_activating_the_Ets_1_through_ERKs_signaling_ L2 - https://dx.plos.org/10.1371/journal.pone.0032624 DB - PRIME DP - Unbound Medicine ER -