Accumulation of Cytoplasmic β-Catenin and Nuclear Glycogen Synthase Kinase 3β in Epstein-Barr Virus-Infected Cells

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Abstract
Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with cancers in immunocompromised populations. EBV establishes a latent infection and immortalizes and transforms B lymphocytes. Several latent proteins have profound effects on cellular growth, including activation of NF-κB, phosphatidylinositol 3′-OH kinase (PI3K) signaling, and notch signaling. Activation of PI3K can affect the activity of β-catenin, the target of the wnt signaling pathway. Deregulation of β-catenin is associated with a number of malignancies. To determine if β-catenin is regulated by EBV infection, EBV-infected cells were examined for β-catenin levels and localization. β-Catenin was increased in EBV-positive tumor cell lines compared to EBV-negative lines, in EBV-infected Burkitt's lymphoma cell lines, and in EBV-transformed lymphoblastoid cell lines (LCL). In contrast to wnt signaling, EBV consistently induced the accumulation of β-catenin in the cytoplasm but not the nucleus. The β-catenin regulating kinase, glycogen synthase kinase 3β (GSK3β), was shown to be phosphorylated and inactivated in EBV-infected lymphocytes. Inactivated GSK3β was localized to the nucleus of EBV-infected LCL. Neither the cytoplasmic accumulation of β-catenin nor the nuclear inactivation of GSK3β was affected by the inhibition of PI3K signaling. These data indicate that latent infection with EBV has unique effects on β-catenin signaling that are distinct from activation of wnt and independent of its effects on PI3K.