title: EBV infection renders B cells resistant to growth inhibition via adenylyl cyclase.
abstract: Cyclic AMP (cAMP) is an important physiological growth inhibitor of lymphoid cells, and the cAMP/protein kinase A (PKA) pathway is disrupted in several immunological disorders and cancers. Epstein Barr virus (EBV) infection of B lymphocytes is responsible for the development of lymphoproliferative disease as well as certain B-lymphoid malignancies. Here we hypothesized that EBV infection might render B lymphocytes resistant to cAMP/PKA-mediated growth inhibition. To test this, we assessed the growth-inhibitory response of cAMP-elevating compounds such as forskolin and isoproterenol, as well as the PKA activator 8-CPT-cAMP in normal B lymphocytes, EBV-infected B cells and in the EBV-negative B lymphoid cell line Reh. We could demonstrate that EBV infection indeed abolished cAMP-mediated growth inhibition of B cells. The defect was pinpointed to defective adenylyl cyclase (AC) activation by forskolin and isoproterenol, resulting in reduced formation of cAMP and lack of PKA activation and CREB phosphorylation. In contrast, 8-CPT-cAMP which directly activates PKA was able to inhibit EBV-infected B cell growth. The physiological implications of these results were underlined by the observation that the ability of forskolin to inhibit camptothecin-induced apoptosis was abolished in EBV-infected B cells. We conclude that EBV infection of B cells abrogates the activation of AC and thereby cAMP formation, and that this dysfunction renders the cells resistant to growth inhibition via the cAMP/PKA pathway.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
authors.forename: Martine Müller
authors.initials: MM
authors.lastname: Kloster
authors.forename: Tilahun Tolesa
authors.initials: TT
authors.lastname: Hafte
authors.forename: Lise Román
authors.initials: LR
authors.lastname: Moltzau
authors.forename: Elin Hallan
authors.initials: EH
authors.lastname: Naderi
authors.forename: Maria Krudtaa
authors.initials: MK
authors.lastname: Dahle
authors.forename: Bjørn Steen
authors.initials: BS
authors.lastname: Skålhegg
authors.forename: Gustav
authors.initials: G
authors.lastname: Gaudernack
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Soheil
authors.initials: S
authors.lastname: Naderi
authors.forename: Heidi Kiil
authors.initials: HK
authors.lastname: Blomhoff
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000821:virology*; D002166:Camptothecin / Q000633:toxicity; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000037:antagonists & inhibitors; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002166:Camptothecin