A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon gamma response genes.
The biological effects of interferon gamma (IFNgamma) are mediated by interferon-stimulated genes (ISGs), many of which are activated downstream of Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling. Herein we have shown that IFNgamma rapidly activated AP-1 DNA binding that required c-Jun but was independent of JAK1 and STAT1. IFNgamma-induced c-Jun phosphorylation and AP-1 DNA binding required the MEK1/2 and ERK1/2 signaling pathways, whereas the JNK1/2 and p38 mitogen-activated protein kinase pathways were dispensable. The induction of several ISGs, including ifi-205 and iNOS, was impaired in IFNgamma-treated c-Jun-/- cells, but others, such as IP-10 and SOCS3, were unaffected, and chromatin immunoprecipitation demonstrated that c-Jun binds to the iNOS promoter following treatment with IFNgamma. Thus, IFNgamma induced JAK1- and STAT1-independent activation of the ERK mitogen-activated protein kinase pathway, phosphorylation of c-Jun, and activation of AP-1 DNA binding, which are important for the induction of a subset of ISGs. This represents a novel signal transduction pathway induced by IFNgamma that proceeds in parallel with conventional JAK/STAT signaling to activate ISGs.
Gough
Daniel J
DJ
Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, and University of Melbourne, Parkville 3054, Victoria, Australia.
Sabapathy
Kanaga
K
Ko
Enoch Yi-No
EY
Arthur
Helen A
HA
Schreiber
Robert D
RD
Trapani
Joseph A
JA
Clarke
Christopher J P
CJ
Johnstone
Ricky W
RW
D000818:Animals; D002461:Cell Line, Transformed; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C509511:Ifi205 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases