The role of EBNA binding proteins in cell transformation

University dissertation from Stockholm : Karolinska Institutet, Dept of Microbiology, Tumor and Cell Biology

Abstract: Epstein - Barr virus (EBV) infects m ajority of the human population and maintains sub - cl inical infection . However , under certain conditions it is associated with several B - cell malignancies , such as Burkitt lymphoma, Hodgkin’s lymphoma etc. Moreover , EBV also plays a causative role in a cquired immunodeficiency syndrome ( AIDS ) associated lymph omas and post - transplant lymphoproliferative disease (PTLD). EBV maintains latent infection and expresses a particular set of proteins that are necessary for host cell proliferation. Studying function of EBV latent proteins could help us to understand the mechanisms underlying EBV induced B - cell transformation. EBV transformed B cells, i.e. lymphoblastoid cell lines (LCLs) is a well - established in vitro model system to study the molecular mechanisms of B - cell transformation. In the present work , we have ide ntified vitamin D receptor (VDR) as a binding p artner of EBNA3. We showed that EBNA3 can block the VDR mediated gene transactivation and protect s B - cells from vitamin D3 induced growth arrest/ apoptosis. We have observed that hypoxia inducible factor 1 alp ha (HIF1 ? ) is stabilized in LCLs at normoxic conditions. HIF1 ?? is not hydroxylated and therefore it is not degraded in LCLs . We have shown that prolylhydroxylases 1 and 2 (PHD1 and 2) that are responsible for hydroxylation of HIF1 ??? form complex es with ??? ???? and ?????? ?? respectively ? ? Due to t his binding catalytic activity of PHDs is block ed , resulting in inhibition of HIF1 ?? hydroxylation and subsequent degradation. Stabilized HIF1 ?? is transcriptionally active and induces genes that are involved in glycolysi s. Moreover , LCLs have high levels of pyruvate and lactate in contrast to mitogen activated B cells , indicating induction of aerobic glycolysis or Warburg effect. We have shown that mitochondrial ribosomal protein MRP S18 - 2 (S18 - 2), an EBNA6 binding protein , can immortalize rat embryonic fibroblasts (REFs). These immortalized cells express stem cell markers like SSEA1, Sox2, Oct3/4 and have the characteristics of embryonic stem cells. S18 - 2 also immortalize d the adult rat skin fibroblasts (RSFs). Moreover, s ingle clones from immortalized REFs and RSFs resulted in tumors in SCID mice. T h i s t hes i s w or k re v ea l s three d i ffere n t aspects of EB V induced B - cell transformation, i .e . pr o t ec ti o n fro m v it a m i n D 3 i ndu c e d apop t o s i s , m e t abo li c a d ap t a ti o n required for proliferation an d hijacking functions of novel protein MRPS18 - 2 for immortalization.

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