Abstract
Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is a proven oncogene that is essential for transformation of human B cells by the virus. LMP1 induces constitutive activation of several signal transduction pathways involving nuclear factor kappaB, phosphatidylinositol 3-kinase/Akt, and the mitogen-activated protein kinases (MAPK) p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (Erk). Sequencing of LMP1 isolated from a panel of EBV+ B cell lymphomas identified three different variants of LMP1, each distinct from the B95.8 prototype isoform. All tumor variants of LMP1 as well as the B95.8 LMP1 isoform were able to induce rapid p38 phosphorylation as well as Akt and JNK activation. Additionally all variants showed similar ability to activate nuclear factor kappaB. In contrast, only tumor-derived LMP1 variants induced prolonged Erk activation and c-Fos expression. Sequence analysis revealed only two amino acids, 212 and 366, shared by the tumor variants but distinct from B95.8. Point mutation of either amino acids 212 (glycine to serine) or 366 (serine to threonine) from the B95.8 isoform to the tumor variant version of LMP1 was sufficient for gain of function characterized by sustained activation of Erk and subsequent c-Fos induction and binding to the AP1 site. Our results indicate that the enhanced ability of tumor-derived LMP1 to induce and stabilize the c-Fos oncogene can be localized to two amino acids in the C terminus of LMP1.
Highlights
Mimics the CD40 receptor, unlike CD40, Latent membrane protein 1 (LMP1) functions in a ligand-independent manner and is constitutively active [4]
Several key sites within the C terminus of LMP1 are necessary for proper signaling including the PXQXT motif in the C-terminal activation region 1 (CTAR1) region which mediates binding of tumor necrosis factor receptor-associated factors (TRAFs) 1, 2, 3, and 5, and tyrosines 384 and 385 of CTAR2 that are essential for TRAF-associated death domain protein (TRADD) interaction, the recruitment of TRAF2, and association of receptor-interacting protein [5,6,7,8,9,10,11]
Characterization of the signaling pathways induced by LMP1 that lead to these outcomes have primarily relied upon the B95.8 prototype variant of LMP1 originally isolated from a patient with infectious mononucleosis
Summary
MF4: RHSDEHHHDDSLPHPQQATDDSSHESDSNSNEGRHHLLVSGAGDGPPLCSQNLGAPGGGPDNGPQDPDNTDD isolated from a patient with infectious mononucleosis [28]. LMP1 is expressed in association with other latent cycle EBV genes in several EBV-associated malignancies including Hodgkin. B95.8: NGPQDPDNTDDNGPHDPL - - - - - - PQDPDNTDDNGPQDPDNTDDNGPQDPDNTDDNGPHDP LPHSPSDSAGN
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