Stat1-independent regulation of gene expression in response to IFN-gamma.
Although Stat1 is essential for cells to respond fully to IFN-gamma, there is substantial evidence that, in the absence of Stat1, IFN-gamma can still regulate the expression of some genes, induce an antiviral state and affect cell growth. We have now identified many genes that are regulated by IFN-gamma in serum-starved Stat1-null mouse fibroblasts. The proteins induced by IFN-gamma in Stat1-null cells can account for the substantial biological responses that remain. Some genes are induced in both wild-type and Stat1-null cells and thus are truly Stat1-independent. Others are subject to more complex regulation in response to IFN-gamma, repressed by Stat1 in wild-type cells and activated in Stat1-null cells. Many genes induced by IFN-gamma in Stat1-null fibroblasts also are induced by platelet-derived growth factor in wild-type cells and thus are likely to be involved in cell proliferation. In mouse cells expressing the docking site mutant Y440F of human IFN-gamma receptor subunit 1, the mouse Stat1 is not phosphorylated in response to human IFN-gamma, but c-myc and c-jun are still induced, showing that the Stat1 docking site is not required for Stat1-independent signaling.
Ramana
C V
CV
Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Gil
M P
MP
Han
Y
Y
Ransohoff
R M
RM
Schreiber
R D
RD
Stark
G R
GR
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early; D016758:Genes, jun; D016259:Genes, myc; D006801:Humans; D017874:Immediate-Early Proteins; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D017471:Receptors, Interferon / Q000502:physiology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
D022782:CCAAT-Enhancer-Binding Protein-beta; D018925:Chemokines; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D007371:Interferon-gamma; D010982:Platelet-Derived Growth Factor; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; C497325:EGR1 protein, human; C486109:Egr1 protein, mouse; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse