Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma.
Type I (alpha, beta) and type II (gamma) interferons (IFNs) can restrict the growth of many cell types. INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus kinase-signal transducers and activators of transcription pathway, in which both IFN-alpha and IFN-gamma activate the transcription factor Stat1. A cell line lacking Stat1 (U3A) was not growth-arrested by IFN-alpha or IFN-gamma, and experiments were carried out with U3A cells permanently expressing normal or various mutant forms of Stat1 protein. Only cells in which complete Stat1 activity was available (Stat1alpha) were growth-inhibited by IFN-gamma. A mutant that supports 20-30% normal transcription did not cause growth restraint. In contrast, IFN-alpha growth restraint was imposed by cells producing Stat1beta, which lacks transcriptional activation potential. This parallels earlier results showing the truncated Stat1 can function in IFN-alpha gene activation. In addition to experiments on long-term cultured cells, we also found that wild-type primary mouse embryonic fibroblasts were inhibited by IFNs, but fibroblasts from Stat1-deficient mouse embryos were not inhibited by IFNs.
Bromberg
J F
JF
Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10021-6399, USA.
Horvath
C M
CM
Wen
Z
Z
Schreiber
R D
RD
Darnell
J E
JE
D000818:Animals; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D004622:Embryo, Mammalian; D005347:Fibroblasts; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D006656:Protamine Kinase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D006656:Protamine Kinase; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D013936:Thymidine