CCAAT/Enhancer-binding Protein β Mediates Interferon-γ-induced p48 (ISGF3-γ) Gene Transcription in Human Monocytic Cells

Abstract

Previous studies have identified a novel interferonstimulated response element-like element, termed ␥-interferon-activating transcription element, within the interferon-stimulating gene factor-3␥ ( Interferon-stimulated gene factor-3 (ISGF3) 1 plays a crucial role in mediating the antiviral, antitumor, and immune responses induced by IFNs. The ISGF3 complex consists of a 48-kDa DNA-binding protein (p48 or ISGF3-␥) and two signal transducer and activators of transcription (STAT) proteins, STAT1 and STAT2. The p48 protein in the ISGF3 complex serves as the adaptor to redirect STAT multimers from their intrinsic palindrome sequence specificity and allows binding to the IFN-stimulated response element (ISRE) that occurs within the promoters of various IFN-stimulated genes (ISGs) (2). In addition to the ISRE element, a distinct cis-element termed IFN-␥-activated site (GAS) is also found within the promoters of many IFN-inducible genes and is bound by the STAT1 homodimer (3). The p48 protein belongs to the interferon regulatory factor (IRF)-myb family of transacting factors. This family of transcription factors can activate (IRF-1 and p48), repress (IRF-2 and interferon consensus sequence-binding protein), both activate and repress (IRF-4), and may activate or repress (IRF-3) transcription of target genes (4). Studies of p48 knockout mice have shown that p48 plays an essential role in both type I and type II IFN responses for activation of IFN-inducible genes and establishment of the antiviral state (5). A recent study showed that an ISRE-like sequence in the hepatitis B viral enhancer-1 could interact with the ISGF3 complex containing p48 and mediate the IFN-␣-induced suppression of enhancer activity (6). Other independent studies also demonstrated that overexpression of p48 in NIH-3T3 cells restored IFN responses of adenovirus E1A-expressing cells in which the IFN signaling was blocked by E1A (7,8). Although IFN and other cytokines induced by the Janus tyrosine kinase-STAT pathway have been well described, the mechanisms regulating expression of the p48 component of ISGF3 remain largely unknown. A number of studies have shown that various cell types, including primary chronic lymphocytic leukemia, human trophoblast, melanoma, and acute promyelocytic leukemia, are resistant to the actions of IFN because the induction of p48 protein is defective (9 -12). Additionally, it has been argued that IFN-␥ priming up-regulates p48-enhanced antiviral and antitumor effects of class I IFNs on IFN-resistant cells (13,14). Furthermore, recent studies have shown that p48 protein also binds to virus-inducible elements within the IFN-␣/␤ promoters. This evidence suggests a potentially new role for ISGF3 in that it may participate directly in the activation of IFN-␣/␤ promoters (15, 16). Therefore, understanding the transcriptional regulation of p48 is very important for elucidating the global functions of IFNs and signaling pathway networks among cytokines.Previously, we demonstrated that a novel IFN-␥-activated transcription element ...

A Novel Transactivating Factor That Regulates Interferon-γ-dependent Gene Expression

“…One of these is a known transcription factor, C/EBP-␤ (22). An independent study also confirmed that C/EBP-␤ stimulates GATE-regulated transcription (23). In this study we have characterized a novel factor, GBF-1.…”

“…A C/EBP-␤ consensus sequence (CBS) is present in GATE (Fig. 5B) and is necessary for stimulating transcription in a variety of cells (22,23). The fact that GM-1, GM-2, and GM-3 do not respond to IFN-␥ and have a disrupted CBS indicates that C/EBP-␤ binding site plays a large role in regulating this promoter.…”

Expression regulation of zebrafish interferon regulatory factor 9 by promoter analysis

“…In mammals, IFNc-induced IRF9 protein expression requires de novo protein synthesis, which results in the discovery of GATE motif-dependent induction of mouse IRF9 (Xiao et al, 1997a). A serial of studies revealed the underlying mechanism: initially, IFNc treatment induces the synthesis of two kinds of transcription factors, C/EBP-b and GBF1, possibly through JAK-STAT signaling pathway; subsequently, the produced transcription factors are activated by IFNc treatment, translocate to nucleus and bind to the GATE motif triggering IRF9 expression (Hu et al, 2002;Kalvakolanu and Roy, 2005;Meng et al, 2005;Roy et al, 2000;Xiao et al, 2001). Therefore, the signaling transduction involved is likely different between GAS-dependent and GATE-dependent induction of zebrafish IRF9 gene by zebrafish IFNc2.…”

“…The expression property of mouse IRF9 correlates with the complexity of its promoter structure, which includes multiple potential regulatory elements including NF-jB, GAS, GATE (IFN-gamma-activated transcriptional element), and Myc/Max elements (Rani et al, 2010). GATE motif is first characterized in mouse IRF9 promoter as a binding site of CAAAT/enhancer binding protein-b (C/EBP-b) (Roy et al, 2000;Xiao et al, 1997aXiao et al, , 2001) and GATE-binding factor 1 (GBF1) (Hu et al, 2002;Meng et al, 2005) in response to IFNc treatment. Both C/EBP-b and GBF1 binding to GATE site significantly promotes IRF9 gene transcription (Meng et al, 2005).…”

Critical Role for Transcription Factor C/EBP-β in Regulating the Expression of Death-Associated Protein Kinase 1

“…Among these proteins, C/EBP-␤ uniquely responds to a variety of extracellular and intracellular signals to mediate a number of responses (37,39). Although the effect of C/EBP-␤ on irf9 is well characterized (70,93), it is not clear whether C/EBP-␤ has any other gene targets in the IFN-signaling pathways. Recently, we noticed that IFN-␥-induced cell death is suppressed significantly in cebpb Ϫ/Ϫ cells, indicating the existence of other potential IFN-induced pathways driven through C/EBP-␤.…”