Abstract
Interferons (IFNs) regulate the expression of a number of cellular genes by activating the JAK-STAT pathway. We have recently discovered that CCAAAT/enhancer-binding protein-beta (C/EBP-beta) induces gene transcription through a novel IFN response element called the gamma-IFN-activated transcriptional element (Roy, S. K., Wachira, S. J., Weihua, X., Hu, J., and Kalvakolanu, D. V. (2000) J. Biol. Chem. 275, 12626-12632. Here, we describe a new IFN-gamma-stimulated pathway that operates C/EBP-beta-regulated gene expression independent of JAK1. We show that ERKs are activated by IFN-gamma to stimulate C/EBP-beta-dependent expression. Sustained ERK activation directly correlated with C/EBP-beta-dependent gene expression in response to IFN-gamma. Mutant MKK1, its inhibitors, and mutant ERK suppressed IFN-gamma-stimulated gene induction through the gamma-IFN-activated transcriptional element. Ras and Raf activation was not required for this process. Furthermore, Raf-1 phosphorylation negatively correlated with its activity. Interestingly, C/EBP-beta-induced gene expression required STAT1, but not JAK1. A C/EBP-beta mutant lacking the ERK phosphorylation site failed to promote IFN-stimulated gene expression. Thus, our data link C/EBP-beta to IFN-gamma signaling through ERKs.
Highlights
Of a number of IFN-stimulated genes (ISGs)
IFN-␥-induced Gene Expression through GATE Is Inhibited by Protein Kinase Inhibitors—To understand the role of protein kinases in IFN-␥-stimulated gene expression through GATE, we studied the influence of staurosporine, a protein kinase inhibitor
Since C/EBP- binds to GATE and induces gene expression [21], we examined whether staurosporine blocks C/EBP--regulated gene expression
Summary
Of a number of IFN-stimulated genes (ISGs). Induction of ISGs occurs primarily due to the activation of the JAK-STAT pathway [1, 2]. Type I (IFN-␣/) and type II (IFN-␥) IFNs bind to distinct cell-surface receptors and activate the signals that up-regulate the expression of ISGs [2]. The STAT2STAT1 dimer dissociates from the receptor and forms a heteromeric complex with a DNA-binding protein, p48 or IFN regulatory factor-9 or ISGF3␥ [3] This complex, known as ISGF3, binds to the IFN-stimulated response element of the ISGs and induces gene expression [1, 2]. Induction of ISGs by IFN-␥ is far more complex than that of IFN-␣/, largely due to the facts that the temporal control of these genes is variable and that, in some cases, blockade of protein synthesis prevents their expression [9] These data suggest that IFN-␥ may activate different transactivating factors in a JAK-STAT-dependent or -independent manner. These data together indicate that C/EBP- is an important component of GATE-dependent gene expression
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