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Progression of the Epstein-Barr Virus

Progression of the Epstein-Barr Virus. Role of the Latent Membrane Protein 1 (LMP1) in activating the PI3K/Akt Pathway Presented by Mitchell Cadet.

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Progression of the Epstein-Barr Virus

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  1. Progression of the Epstein-Barr Virus Role of the Latent Membrane Protein 1 (LMP1) in activating the PI3K/Akt Pathway Presented by Mitchell Cadet Dawson D.W., G. Tramountanis, A.G. Eliopoulos, and L.S. Young. 2002. Epstein-Barr Virus Latent Membrane Protein 1(LMP1)Activates the Phosphatidylinositol 3-Kinase/Akt Pathway to Promote Cell Survival and Induce Actin Filament Remodeling. Journal of Biological Chemistry. 278:3694-3704

  2. Brief History • 1958 Michael Burkitt discovers malignant tumor in African Children • Michael Epstein & Yvonne Barr cultures a virus with typical herpesvirus morphology • A lab technician acquires mononucleosis while working with Burkitt’s lymphoma virus

  3. Description • Ubiquitous herpesvirus associated with the development of tumors • Circular form of DNA which becomes spliced into the host cell DNA • Exploits the process of B cell development

  4. Epidemiology • Direct oral contact & contamination with saliva • Entry site is the oropharynx • Moves to the parotid gland • Remains latent in the throat and blood

  5. Two Key Proteins • LMP1 • LMP2 • Colonizes memory B cells, provides essential survival signals

  6. LMP1 • Integral membrane protein • Major transforming protein of EBV • Drives resting B cells out of their resting state • Activates the PI3K/Akt Pathway

  7. Phosphatidylinositol 3-Kinase (PI3K), activates cellular processes in response to extracellular stimuli Regulates actin cytoskeletal organization and cell shape remodeling A downstream target of PI3K responsible for promoting cell survival PI3K & Akt

  8. Purpose • Is LMP1 Sufficient to Activate the PI3K/Akt Pathway?

  9. Methods/Resources • LMP1 Chimeric Protein in Rat-1 Cells • Immunostaining of Microinjected Cells for LMP1 and Actin • Western Blotting • Determination of Cell Viability

  10. Expression of LMP1 & Activation of PI3K/Akt Pathway

  11. Findings • Levels of PI3K activity significantly greater in LMP1-expressing cells • Elevated PI3K activity correlated with activation of Akt • Greater levels of Akt activity in LMP1-expressing cells

  12. LMP1-induced Cells & Level of PI3K Activity

  13. Findings • Hours after LMP1 is induced, the level of PI3K activity climbs 2-3 fold

  14. Exposure of LMP1-expressing Rat1 Cells and Cell Viability

  15. Findings • As the dosage of LMP1 positive cells increases, the percent of viable cells decrease dramatically

  16. Discussion • LMP1 has been shown to activate the PI3K/Akt pathway • Evidenced by increased activity in cells expressing LMP1 and the ability of inducible LMP1 expression to also stimulate PI3K activity

  17. Significance • Consequence: the ability of LMP1 to induce morphological transformation in Rat-1 cells • Ability to induce actin reorganization likely to contribute to the establishment of EBV persistence in memory B cell pool

  18. Conclusion • Because of the effects of PI3K on cell survival and proliferation EBV is able to target and manipulate this pathway for efficient promotion of infection and replication

  19. Time!

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