scholarly journals A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site.

1994 ◽  
Vol 14 (2) ◽  
pp. 1364-1373 ◽  
Author(s):  
A Eilers ◽  
M Baccarini ◽  
F Horn ◽  
R A Hipskind ◽  
C Schindler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Dna Binding ◽  
Binding Protein ◽  
Trna Synthetase ◽  
Gamma Interferon ◽  
U937 Cells ◽  
Gamma Activation ◽  
Ifn Gamma ◽  
Differentiation Factors ◽  
Activation Site

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.

A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site

1994 ◽  
Vol 14 (2) ◽  
pp. 1364-1373
Author(s):  
A Eilers ◽  
M Baccarini ◽  
F Horn ◽  
R A Hipskind ◽  
C Schindler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Dna Binding ◽  
Binding Protein ◽  
Trna Synthetase ◽  
Gamma Interferon ◽  
U937 Cells ◽  
Gamma Activation ◽  
Ifn Gamma ◽  
Differentiation Factors ◽  
Activation Site

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.

The response of gamma interferon activation factor is under developmental control in cells of the macrophage lineage

1993 ◽  
Vol 13 (6) ◽  
pp. 3245-3254
Author(s):  
A Eilers ◽  
D Seegert ◽  
C Schindler ◽  
M Baccarini ◽  
T Decker
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Gamma Interferon ◽  
U937 Cells ◽  
Monocytic Differentiation ◽  
Ifn Gamma ◽  
Exonuclease Iii ◽  
Activation Factor ◽  
Gel Shift

Gamma interferon activation factor (GAF) rapidly induces transcriptional activation of gamma interferon (IFN-gamma)-responsive genes. Conversion of the GAF from a latent cytoplasmic to an activated, DNA-binding form is an immediate step in the cellular response to IFN-gamma. The amount of IFN-gamma-activated GAF, measured by exonuclease III protection or gel shift assays, increased strongly upon monocytic differentiation of U937 cells. Activated GAF contained the IFN-responsive 91-kDa protein as its DNA-binding activity in gel shift or exonuclease III assays could be inhibited through direct addition of specific antiserum, and it was not present in p91-immunodepleted extracts. There was a differentiation-induced increase in the amount of nonphosphorylated (latent) p91. Transcription rate measurement demonstrated a strong induction of the p91 gene during monocytic differentiation of U937 cells. The amount of p91 which was rapidly phosphorylated in response to IFN-gamma was found to be much higher in the differentiated cells and suggested a differentiation-controlled increase in the signaling leading to p91 phosphorylation. Concomitantly with a better GAF response, transcriptional activation of IFN-gamma-induced genes and the expression of GAF-dependent, transfected reporter plasmids increased in differentiated U937 monocytes. The promonocyte-monocyte transition also affected the IFN-alpha-responsive transcription factor ISGF-3. Differentiated U937 cells contained more of both the alpha-component p91 and the gamma-component p48, which constitutes the DNA-binding subunit of the complex. Our study thus provides evidence that the synthesis of specific transcription factors can be a regulated event to control the cytokine responsiveness of cells during development.

scholarly journals The response of gamma interferon activation factor is under developmental control in cells of the macrophage lineage.

1993 ◽  
Vol 13 (6) ◽  
pp. 3245-3254 ◽  
Author(s):  
A Eilers ◽  
D Seegert ◽  
C Schindler ◽  
M Baccarini ◽  
T Decker
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Gamma Interferon ◽  
U937 Cells ◽  
Monocytic Differentiation ◽  
Ifn Gamma ◽  
Exonuclease Iii ◽  
Activation Factor ◽  
Gel Shift

Gamma interferon activation factor (GAF) rapidly induces transcriptional activation of gamma interferon (IFN-gamma)-responsive genes. Conversion of the GAF from a latent cytoplasmic to an activated, DNA-binding form is an immediate step in the cellular response to IFN-gamma. The amount of IFN-gamma-activated GAF, measured by exonuclease III protection or gel shift assays, increased strongly upon monocytic differentiation of U937 cells. Activated GAF contained the IFN-responsive 91-kDa protein as its DNA-binding activity in gel shift or exonuclease III assays could be inhibited through direct addition of specific antiserum, and it was not present in p91-immunodepleted extracts. There was a differentiation-induced increase in the amount of nonphosphorylated (latent) p91. Transcription rate measurement demonstrated a strong induction of the p91 gene during monocytic differentiation of U937 cells. The amount of p91 which was rapidly phosphorylated in response to IFN-gamma was found to be much higher in the differentiated cells and suggested a differentiation-controlled increase in the signaling leading to p91 phosphorylation. Concomitantly with a better GAF response, transcriptional activation of IFN-gamma-induced genes and the expression of GAF-dependent, transfected reporter plasmids increased in differentiated U937 monocytes. The promonocyte-monocyte transition also affected the IFN-alpha-responsive transcription factor ISGF-3. Differentiated U937 cells contained more of both the alpha-component p91 and the gamma-component p48, which constitutes the DNA-binding subunit of the complex. Our study thus provides evidence that the synthesis of specific transcription factors can be a regulated event to control the cytokine responsiveness of cells during development.

scholarly journals The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds.

1993 ◽  
Vol 13 (7) ◽  
pp. 3951-3963 ◽  
Author(s):  
Y Kanno ◽  
C A Kozak ◽  
C Schindler ◽  
P H Driggers ◽  
D L Ennist ◽  
...  
Keyword(s):  
Gamma Interferon ◽  
Chromosome 8 ◽  
Alpha Subunit ◽  
Upstream Region ◽  
Lymphoid Tissues ◽  
Type I ◽  
Gamma Activation ◽  
Response Element ◽  
Ifn Gamma ◽  
Activation Site

ICSBP, a member of the interferon regulatory factor family, is expressed predominantly in lymphoid tissues and is induced by gamma interferon (IFN-gamma). We have studied the genomic organization of the murine ICSBP gene and its 5' upstream region. The murine ICSBP gene (Icsbp) is present as a single copy on chromosome 8 and consists of nine exons. Transcription initiates at two juxtaposed sites downstream from the TATA and CAAT boxes and produces two species of ICSBP mRNA (3.0 and 1.7 kb), presumably by differential usage of poly(A)+ signals. A sequence from -175 to -155 was identified to be an IFN response region that conferred IFN-gamma induction upon a heterologous promoter in lymphoid cell line EL4. This region includes a motif, TTCNNGGAA, designated the palindromic IFN response element (pIRE), to which an IFN-gamma-inducible, cycloheximide-sensitive factor(s) binds. A similar palindromic motif was found in the upstream region of the murine IRF-1 gene, the IFN-gamma activation site of the guanylate-binding protein gene and the IFN-gamma-responsive region of the Fc receptor type I gene, all of which competed with the pIRE for factor binding in gel mobility shift assays. We show that the pIRE binding factor reacts with the antibody against the 91-kDa subunit of ISGF3 alpha recently shown to bind to the IFN-gamma activation site. These results suggest that this factor is related to the IFN-gamma activation factor and contains the 91-kDa subunit of ISGF3 alpha. Taken together, pIRE represents an IRE that is distinct from the classical IFN-stimulated response element and that is capable of conferring IFN-gamma induction through the binding of the 91-kDa ISGF3 alpha subunit (or an antigenically similar molecule).

The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds

1993 ◽  
Vol 13 (7) ◽  
pp. 3951-3963
Author(s):  
Y Kanno ◽  
C A Kozak ◽  
C Schindler ◽  
P H Driggers ◽  
D L Ennist ◽  
...  
Keyword(s):  
Gamma Interferon ◽  
Chromosome 8 ◽  
Alpha Subunit ◽  
Upstream Region ◽  
Lymphoid Tissues ◽  
Type I ◽  
Gamma Activation ◽  
Response Element ◽  
Ifn Gamma ◽  
Activation Site

ICSBP, a member of the interferon regulatory factor family, is expressed predominantly in lymphoid tissues and is induced by gamma interferon (IFN-gamma). We have studied the genomic organization of the murine ICSBP gene and its 5' upstream region. The murine ICSBP gene (Icsbp) is present as a single copy on chromosome 8 and consists of nine exons. Transcription initiates at two juxtaposed sites downstream from the TATA and CAAT boxes and produces two species of ICSBP mRNA (3.0 and 1.7 kb), presumably by differential usage of poly(A)+ signals. A sequence from -175 to -155 was identified to be an IFN response region that conferred IFN-gamma induction upon a heterologous promoter in lymphoid cell line EL4. This region includes a motif, TTCNNGGAA, designated the palindromic IFN response element (pIRE), to which an IFN-gamma-inducible, cycloheximide-sensitive factor(s) binds. A similar palindromic motif was found in the upstream region of the murine IRF-1 gene, the IFN-gamma activation site of the guanylate-binding protein gene and the IFN-gamma-responsive region of the Fc receptor type I gene, all of which competed with the pIRE for factor binding in gel mobility shift assays. We show that the pIRE binding factor reacts with the antibody against the 91-kDa subunit of ISGF3 alpha recently shown to bind to the IFN-gamma activation site. These results suggest that this factor is related to the IFN-gamma activation factor and contains the 91-kDa subunit of ISGF3 alpha. Taken together, pIRE represents an IRE that is distinct from the classical IFN-stimulated response element and that is capable of conferring IFN-gamma induction through the binding of the 91-kDa ISGF3 alpha subunit (or an antigenically similar molecule).

In vitro activation of the transcription factor gamma interferon activation factor by gamma interferon: evidence for a tyrosine phosphatase/kinase signaling cascade

1993 ◽  
Vol 13 (3) ◽  
pp. 1634-1640
Author(s):  
K Igarashi ◽  
M David ◽  
D S Finbloom ◽  
A C Larner
Keyword(s):  
Tyrosine Phosphatase ◽  
Gamma Interferon ◽  
Cell Surface Receptor ◽  
Signaling Cascade ◽  
Kinase Signaling ◽  
Gamma Activation ◽  
Ifn Gamma ◽  
Genistein Treatment ◽  
Activation Factor

Although it has been well documented that the biological activities of gamma interferon (IFN-gamma) are initiated through interaction with its cell surface receptor, the signal transduction mechanisms which mediate the effects of this cytokine have remained unclear. In order to facilitate a better understanding of IFN-gamma signaling, we have designed an assay using human fibroblast cell homogenates in which IFN-gamma activates the formation of the IFN-gamma activation factor (GAF) transcription complex. GAF mediates the rapid transcriptional activation of the guanylate-binding protein gene by IFN-gamma. Activation of GAF in homogenates required ATP, but not Ca2+ or GTP. Fractionation of homogenates indicated that both the pellet (18,000 x g) and the remaining cytoplasmic fraction were required for GAF activation by IFN-gamma. In intact cells and cell homogenates, the activation of GAF was prevented by the specific tyrosine kinase inhibitor genistein. Treatment of GAF-containing nuclear extracts with either monoclonal antiphosphotyrosine antibody or protein tyrosine phosphatase prevented the assembly of the transcription complex, indicating that its formation required phosphorylation of tyrosine residues. Furthermore, the tyrosine phosphatase inhibitors phenylarsine oxide and zinc chloride also inhibited GAF formation in vitro, but only if these agents were added to cell homogenates before IFN-gamma was added. The addition of either agent 5 min after IFN-gamma had no effect. These results provide the first evidence for an IFN-gamma-regulated tyrosine phosphatase/kinase signaling cascade that permits this cytokine to activate the transcription of an early-response gene.

scholarly journals The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element.

1996 ◽  
Vol 16 (9) ◽  
pp. 4744-4753 ◽  
Author(s):  
J Ye ◽  
M Cippitelli ◽  
L Dorman ◽  
J R Ortaldo ◽  
H A Young
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Dna Sequences ◽  
Promoter Activity ◽  
Cell Activation ◽  
Gamma Interferon ◽  
Nuclear Factor ◽  
Enhancer Activity ◽  
Ifn Gamma ◽  
Silencer Element

Our group has previously reported that the nuclear factor Yin-Yang 1 (YY1), a ubiquitous DNA-binding protein, is able to interact with a silencer element (BE) in the gamma interferon (IFN-gamma) promoter region. In this study, we demonstrated that YY1 can directly inhibit the activity of the IFN-gamma promoter by interacting with multiple sites in the promoter. In cotransfection assays, a YY1 expression vector significantly inhibited IFN-gamma promoter activity. Mutation of the YY1 binding site in the native IFN-gamma promoter was associated with an increase in the IFN-gamma promoter activity. Analysis of the DNA sequences of the IFN-gamma promoter revealed a second functional YY1 binding site (BED) that overlaps with an AP1 binding site. In this element, AP1 enhancer activity was suppressed by YY1. Since the nuclear level of YY1 does not change upon cell activation, our data support a model that the nuclear factor YY1 acts to suppress basal IFN-gamma transcription by interacting with the promoter at multiple DNA binding sites. This repression can occur through two mechanisms: (i) cooperation with an as-yet-unidentified AP2-like repressor protein and (ii) competition for DNA binding with the transactivating factor AP1.

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