A Positive Autoregulatory Loop of LMP1 Expression and STAT Activation in Epithelial Cells Latently Infected with Epstein-Barr Virus

Abstract

Epstein-Barr virus (EBV) is associated with a variety of human malignancies (62). In settings such as posttransplant lymphoproliferative disease, where the full latency III program is expressed, EBV nuclear-associated protein 2 (EBNA2) and LMP1 make critical contributions (10, 41). The Cp promoter that drives EBNA2 expression along with that of EBNA-LP and EBNA3A, -3B, and -3C is regulated by EBNA2 (39, 52, 72), as are the promoters for LMP1 and LMP2A (40,49,85,91). EBNA2 also contributes to dysregulated cellular growth proliferation and provides a cell survival function. EBNA2 is a transcriptional activator that targets responsive promoters through interactions with the cell DNA-binding proteins Pu.1 and CBF1 (RBPJ-) (20, 26, 31,48,83,92).In targeting CBF1, EBNA2 mimics activated Notch, NotchIC, and thus EBNA2 can modify cellular gene transcription in a manner that resembles constitutively activated Notch signaling (24, 32, 37,71,90). NotchIC has a separate antiapoptotic activity mediated through targeting of the immediateearly response factor Nur77 (38), and this activity is also demonstrated by EBNA2 (50).LMP1 functions as a constitutively active tumor necrosis factor receptor and mimics aspects of CD40 signaling (15, 23,58,81). The cytoplasmic carboxy terminus of LMP1 contains two effector domains, CTAR1 and CTAR2, that interact with tumor necrosis factor receptor-associated factors and with tumor necrosis factor receptor-associated death domain and receptor interacting protein, respectively, to activate NF-B, p38 mitogen-activated protein kinase, and JNK pathways (12,14, 16, 22, 33, 35, 36,43,56,73). As a downstream consequence of these pathways, LMP1 provides a cell survival function through upregulation of antiapoptotic proteins such as Bcl-2, Mcl-1, Bfl-1, and A20 (13, 18, 25,47,86) and alters cell growth through induction of epidermal growth factor receptor and cytokines such as interleukin-6 (IL-6) (16, 17, 28,55). Another

Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

“…Numerous studies have also demonstrated that EBV-derived LMP1 can mediate STAT3 activation in EBV infection through several signaling pathways [9,23]. Finally, we examined whether EBNA2 cooperatively acts on STAT3 with EBV-derived LMP1.…”

“…STAT3 activation has been reported to play roles in the development of human herpesvirus-associated diseases [9,23]. Our previous study demonstrated that a Kaposi's sarcoma-associated herpesvirus (KSHV)-derived nuclear protein, LANA, directly interacts with STAT3 and augments its transcriptional activation [20].…”

“…Our previous study demonstrated that a Kaposi's sarcoma-associated herpesvirus (KSHV)-derived nuclear protein, LANA, directly interacts with STAT3 and augments its transcriptional activation [20]. EBV-derived LMP1 has also been shown to mediate STAT3 activation [9,23]. These findings led us to investigate the effects of the EBV-derived nuclear protein EBNA2 on STAT3 activation.…”

The Viral Etiology of AIDS‐Associated Malignancies

“…Several viral genes, such as LMP-1 and EBNA-2, are required for the transformation of primary B cells in vitro and are believed to drive EBV transformation process in vivo. EBV contributes to the cellular transformation processes through the activity of viral proteins that act cooperatively to modify cellular gene expression that involved in cell proliferation, apoptosis, angiogenesis, immune regulation, and signal transduction (Cahir-McFarland et al, 2000;Chen et al, 2003;Fries et al, 1996;Henderson et al, 1991;Miller et al, 1995;Wang et al, 1985Wang et al, , 1990Yoshizaki et al, 1998;Zhang and Pagano, 1999;Zhang et al, 2004a,c).…”

Activation of Stat3 Transcription Factor by Herpesvirus Saimiri STP-A Oncoprotein

“…Furthermore, it has been shown that Stat3 exerts its growth-deregulating activity by activating the expression of cellular genes that are involved in cell cycle progression such as fos, cyclin D1, myc, and pim-1 and by activating antiapoptotic processes such as Bcl-2 and Bcl-XL (3,5,7,17,35). Thus, activation of the Stat3 signal transduction pathway is likely a common strategy used by various viruses to transform a normal cell to a cancerous cell (8,38). In fact, viral Src has been shown to interact with Stat3 and to activate Stat3 to induce cell growth transformation (4,34,37).…”