RRC ID 11793
Author Umehara D, Watanabe S, Ochi H, Anai Y, Ahmed N, Kannagi M, Hanson C, Ruscetti S, Nishigaki K.
Title Role of phosphatidylinositol 3-kinase in friend spleen focus-forming virus-induced erythroid disease.
Journal J. Virol.
Abstract Infection of erythroid cells by Friend spleen focus-forming virus (SFFV) leads to acute erythroid hyperplasia in mice due to expression of its unique envelope glycoprotein, gp55. Erythroid cells expressing SFFV gp55 proliferate in the absence of their normal regulator, erythropoietin (Epo), because of interaction of the viral envelope protein with the erythropoietin receptor and a short form of the receptor tyrosine kinase Stk (sf-Stk), leading to constitutive activation of several signal transduction pathways. Our previous in vitro studies showed that phosphatidylinositol 3-kinase (PI3-kinase) is activated in SFFV-infected cells and is important in mediating the biological effects of the virus. To determine the role of PI3-kinase in SFFV-induced disease, mice deficient in the p85alpha regulatory subunit of class IA PI3-kinase were inoculated with different strains of SFFV. We observed that p85alpha status determined the extent of erythroid hyperplasia induced by the sf-Stk-dependent viruses SFFV-P (polycythemia-inducing strain of SFFV) and SFFV-A (anemia-inducing strain of SFFV) but not by the sf-Stk-independent SFFV variant BB6. Our data also indicate that p85alpha status determines the response of mice to stress erythropoiesis, consistent with a previous report showing that SFFV uses a stress erythropoiesis pathway to induce erythroleukemia. We further showed that sf-Stk interacts with p85alpha and that this interaction depends upon sf-Stk kinase activity and tyrosine 436 in the multifunctional docking site. Pharmacological inhibition of PI3-kinase blocked proliferation of primary erythroleukemia cells from SFFV-infected mice and the erythroleukemia cell lines derived from them. These results indicate that p85alpha may regulate sf-Stk-dependent erythroid proliferation induced by SFFV as well as stress-induced erythroid hyperplasia.
Volume 84(15)
Pages 7675-82
Published 2010-8
DOI 10.1128/JVI.00488-10
PII JVI.00488-10
PMID 20504929
PMC PMC2897631
MeSH Animals Cell Line, Tumor Leukemia, Erythroblastic, Acute / virology* Mice Mice, Inbred BALB C Phosphatidylinositol 3-Kinases / deficiency Phosphatidylinositol 3-Kinases / metabolism* Receptor Protein-Tyrosine Kinases / metabolism* Spleen Focus-Forming Viruses / pathogenicity*
IF 4.368
Times Cited 5