title: Dual regulatory roles of phosphatidylinositol 3-kinase in IFN signaling.
abstract: PI3K is activated by the type I and II IFN receptors, but its precise role in the generation of IFN responses is not well understood. In the present study we used embryonic fibroblasts from mice with targeted disruption of the genes encoding for both the p85alpha and p85beta regulatory subunits of PI3'-kinase (p85alpha(-/-)beta(-/-)) to precisely define the role of PI3K in the control of IFN-induced biological responses. Our data demonstrate that PI3K plays dual regulatory roles in the induction of IFN responses by controlling both IFN-alpha- and IFN-gamma-dependent transcriptional regulation of IFN-sensitive genes and simultaneously regulating the subsequent initiation of mRNA translation for such genes. These processes include the Isg15, Cxcl10, and/or Irf7 genes, whose functions are important in the generation of the biological effects of IFNs. Consistent with this, the induction of IFN antiviral responses is defective in double p85alpha/p85beta knockout cells. Thus, integration of signals via PI3K is a critical event during engagement of the IFN receptors that complements both the transcriptional activity of Jak-STAT pathways and controls initiation of mRNA translation.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Antonella
authors.initials: A
authors.lastname: Sassano
authors.forename: Ajith M
authors.initials: AM
authors.lastname: Joseph
authors.forename: Beata
authors.initials: B
authors.lastname: Majchrzak-Kita
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Brachmann
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018188:Cardiovirus Infections / Q000276:immunology; D004686:Encephalomyocarditis virus / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D015870:Gene Expression; D005786:Gene Expression Regulation; D007372:Interferons / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D007372:Interferons; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt