Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Virol. 2011 May;85(9):4399-408. doi: 10.1128/JVI.01703-10. Epub 2011 Feb 9.
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects more than 90% of the world's adult population and is linked to multiple malignancies, including Burkitt lymphoma, Hodgkin disease, and nasopharyngeal carcinoma (NPC). The EBV oncoprotein LMP1 induces transcription of the epidermal growth factor receptor (EGFR), which is expressed at high levels in NPC. EGFR transcription is induced by LMP1 through a p50 NFκB1-Bcl-3 complex, and Bcl-3 is induced by LMP1-mediated activation of STAT3. This study reveals that LMP1, through its carboxyl-terminal activation domain 1 (LMP1-CTAR1), activates both STAT3 and EGFR in a serum-independent manner with constitutive serine phosphorylation of STAT3. Upon treatment with EGF, the LMP1-CTAR1-induced EGFR was additionally phosphorylated and STAT3 became phosphorylated on tyrosine, concomitant with upregulation of a subset of STAT3 target genes. The kinase responsible for LMP1-CTAR1-mediated serine phosphorylation of STAT3 was identified to be PKCδ using specific RNAi, a dominant negative PKCδ, and the PKCδ inhibitor rottlerin. Interestingly, inhibition of PKCδ also inhibited constitutive phosphorylation of EGFR and LMP1-CTAR1-induced phosphorylation of ERK. Inhibition of PKCδ blocked LMP1-CTAR1-mediated transformation of Rat-1 cells, likely through the inhibition of ERK activation. These findings indicate that LMP1 activates multiple distinct signaling pathways and suggest that PKCδ functions as a master regulator of EGFR, STAT3, and ERK activation by LMP1-CTAR1.
EB 病毒（EBV）是一种普遍存在的疱疹病毒，感染了世界上超过 90%的成年人，与多种恶性肿瘤有关，包括伯基特淋巴瘤、霍奇金病和鼻咽癌（NPC）。EBV 癌蛋白 LMP1 诱导表皮生长因子受体（EGFR）的转录，EGFR 在 NPC 中高表达。LMP1 通过 p50 NFκB1-Bcl-3 复合物诱导 EGFR 转录，Bcl-3 由 LMP1 介导的 STAT3 激活诱导。本研究表明，LMP1 通过其羧基末端激活结构域 1（LMP1-CTAR1），以非依赖血清的方式激活 STAT3 和 EGFR，同时 STAT3 发生持续的丝氨酸磷酸化。在用 EGF 处理后，LMP1-CTAR1 诱导的 EGFR 被进一步磷酸化，STAT3 酪氨酸残基磷酸化，同时部分 STAT3 靶基因上调。使用特异性 RNAi、显性失活 PKCδ 和 PKCδ 抑制剂 rottlerin，鉴定出负责 LMP1-CTAR1 介导的 STAT3 丝氨酸磷酸化的激酶为 PKCδ。有趣的是，PKCδ 的抑制也抑制了 EGFR 的组成性磷酸化和 LMP1-CTAR1 诱导的 ERK 磷酸化。PKCδ 的抑制阻断了 LMP1-CTAR1 介导的 Rat-1 细胞转化，可能是通过抑制 ERK 激活。这些发现表明 LMP1 激活了多种不同的信号通路，并表明 PKCδ 作为 LMP1-CTAR1 激活 EGFR、STAT3 和 ERK 的主调节因子发挥作用。
