Phosphorylation and nuclear translocation of STAT3 regulated by the Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma.
The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) oncoprotein has been shown to mediate activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we delineated the mechanism by which LMP1 stimulates STAT3 in a human nasopharyngeal carcinoma (NPC) cell line. LMP1 stimulated STAT3 Tyr 705-dependent nuclear accumulation, as well as the phosphorylation of STAT3 at both Tyr 705 and Ser 727. Treatment of cells with interleukin-6 neutralizing antibody inhibited the phosphorylation of STAT3 Tyr 705 and Ser 727. The differential phosphorylation of STAT3 was found to be a result of activation of Janus kinase 3 (JAK3) and extracellular signal-regulated kinase (ERK). The biological significance of JAK3-mediated activation of STAT3 Tyr 705 phosphorylation was further assessed by treating the cells with an inhibitor (WHI-P131) of JAK3. Inhibition of ERK activity by an inhibitor (PD98059) of MAPK/extracellular signal-regulated kinase kinase (MEK1) decreased the LMP1-induced activation of STAT3 Ser 727. Furthermore, immunohistochemical analysis showed an increased nuclear STAT3 Tyr 705 staining in LMP1-positive cells and STAT3 Tyr 705 phosphorylation related to NPC stages III and IV. Demonstration of the involvement of different kinases in LMP1-induced STAT3 activation supports the involvement of the JAK/STAT and mitogen-activated protein kinase (MAPK)/ERK signaling pathways in the regulation of STAT3 activation by LMP1.
Liu
Yi-Ping
YP
Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan 410078, PR China.
Tan
Yun-Nian
YN
Wang
Zhen-Lian
ZL
Zeng
Liang
L
Lu
Zhong-Xin
ZX
Li
Li-Li
LL
Luo
Wei
W
Tang
Min
M
Cao
Ya
Y
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D004790:Enzyme Induction; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D053612:Janus Kinases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009367:Neoplasm Staging; D009500:Neutralization Tests; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D021381:Protein Transport; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015850:Interleukin-6; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; D014763:Viral Matrix Proteins; D010768:Phosphoserine; D019000:Phosphotyrosine; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases