Colony‐stimulating factors and interferon‐γ activate a protein related to MGF‐Stat 5 to cause formation of the differentiation‐induced factor in myeloid cells

Barahmand‐pour, Fariba; Meinke, Andreas; Eilers, Andreas; Gouilleux, Fabrice; Groner, Bernd; Decker, Thomas

doi:10.1016/0014-5793(95)00072-h

Cited by 41 publications

(23 citation statements)

References 37 publications

(47 reference statements)

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“…Promonocytes or monocytes were treated with IFN-␥ for 30 min, and cell extracts were reacted with an excess of labeled IFP53 GAS. DIF is a second IFN-␥-activated factor predominantly found in promonocytes (2,9). (b) Immunoprecipitation (I.P.…”

Section: Resultsmentioning

confidence: 99%

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Differentiation-Regulated Serine Phosphorylation of STAT1 Promotes GAF Activation in Macrophages

Eilers

Georgellis

Klose

et al. 1995

Molecular and Cellular Biology

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Gamma interferon (IFN-␥), a macrophage-activating cytokine, modulates gene expression through the activity of a transcription factor designated IFN-␥ activation factor (GAF). GAF is formed after phosphorylation on tyrosine and dimerization of the 91-kDa protein STAT1. We have recently reported that differentiation of the promonocytic cell line U937 into monocytes increases the amount of cellular GAF after IFN-␥ treatment and at the same time increases the phosphorylation of STAT1. Here we show that activation of the JAK family kinases, which are instrumental in mediating STAT1 phosphorylation on tyrosine, did not increase upon monocytic U937 differentiation. Consistent with this finding, levels of STAT1 tyrosine phosphorylation were virtually identical in promonocytic and monocytic U937 cells. Analysis of STAT1 phosphoamino acids and mapping of phosphopeptides showed an IFN-␥-dependent increase in Ser phosphorylation in differentiated cells. Analyses of STAT1 isoforms by two-dimensional gel electrophoresis demonstrated a differentiationinduced shift toward more acidic isoforms. All isoforms were equally sensitive to subsequent tyrosine phosphorylation, as indicated by a sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility shift typical for tyrosine-phosphorylated STAT1. Consistent with the importance of Ser phosphorylation for high-affinity binding to the IFN-␥ activation site sequence, phosphatase 2A treatment strongly reduced the formation of IFN-␥ activation site-GAF complexes in an electrophoretic mobility shift assay. Our data indicate that the activity of GAF is modulated by STAT1 serine kinases/phosphatases and suggest that this mechanism is employed in the developmental control of macrophage responsiveness to IFN-␥.The cytokine gamma interferon (IFN-␥) is produced by activated natural killers or T H1 cells in the course of the immune response. It exerts a broad range of biological functions, including antiviral activity and an antiproliferative effect leading to growth inhibition and cellular differentiation (reviewed in references 8 and 36). Studies in mice with targeted disruption of either the IFN-␥ gene or the IFN-␥ receptor gene support the conclusion that one major role of IFN-␥ is that as a macrophage-activating factor (5, 13). Activated macrophages acquire physiological properties relevant to their antimicrobial or antitumor cytotoxicity as well as the potential to present antigen (1). This activation response to IFN-␥ is found only in differentiated cells and is acquired during macrophage development.De novo gene expression is an essential part of the response to IFN-␥, and several IFN-␥-inducible genes have been characterized (reviewed in reference 23). An important mechanism for the transcriptional activation of such genes operates through a promoter element designated the IFN-␥ activation site (GAS) (18,23). This sequence binds an IFN-␥-activated transcription factor (GAF) containing a dimer of tyrosinephosphorylated STAT1 protein (p91) (6; reviewed in references 7 and 28). Dime...

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Section: Resultsmentioning

confidence: 99%

“…5; reasons for the decrease in DIF activity in the presence of inhibitors are under investigation). DIF is a STAT family protein requiring phosphorylated tyrosine for DNA binding (2,9). Therefore, the reduction of GAF DNA binding by PP-2a cannot be due to an unspecific pTyr phosphatase activity of PP-2a.…”

Section: Resultsmentioning

confidence: 99%

Differentiation-Regulated Serine Phosphorylation of STAT1 Promotes GAF Activation in Macrophages

Eilers

Georgellis

Klose

et al. 1995

Molecular and Cellular Biology

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“…In addition to being activated by PRL (Kazansky et al 1999), STAT5A/B are activated by interleukin-2 (IL-2; Hou et al 1995), IL-3 , IL-5 (Mui et al 1995)), and IL-7 (Foxwell et al 1995), granulocyte-macrophage colony-stimulating factor (Barahmand-pour et al 1995, insulin (Wartmann et al 1996), erythropoietin (Wakao et al 1994, Gouilleux et al 1995b, Pallard et al 1995b, thrombopoietin (Pallard et al 1995a), and GH (Gouilleux et al 1995b, Galsgaard et al 1996 (Table 3). Initially, insight into the distinct roles of STAT5A/B in mediating biological responses was gleaned mainly from gene targeting studies, which revealed that the phenotypes of Stat5a/b knockout (KO) mice are not fully functionally redundant.…”

Section: Structure and Function Of Stat5a/b Proteinsmentioning

confidence: 99%

Signal transducer and activator of transcription 5A/B in prostate and breast cancers

Tan

Nevalainen

2008

Endocrine Related Cancer

100

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Protein kinase signaling pathways, such as Janus kinase 2-Signal transducer and activator of transcription 5A/B (JAK2-STAT5A/B), are of significant interest in the search for new therapeutic strategies in both breast and prostate cancers. In prostate cancer, the components of the JAK2-STAT5A/B signaling pathway provide molecular targets for small-molecule inhibition of survival and growth signals of the cells. At the same time, new evidence suggests that the STAT5A/B signaling pathway is involved in the transition of organ-confined prostate cancer to hormonerefractory disease. This implies that the active JAK2-STAT5A/B signaling pathway potentially provides the means for pharmacological intervention of clinical prostate cancer progression. In addition, active STAT5A/B may serve as a prognostic marker for identification of those primary prostate cancers that are likely to progress to aggressive disease. In breast cancer, the role of STAT5A/B is more complex. STAT5A/B may have a dual role in the regulation of malignant mammary epithelium. Data accumulated from mouse models of breast cancer suggest that in early stages of breast cancer STAT5A/B may promote malignant transformation and enhance growth of the tumor. This is in contrast to established breast cancer, where STAT5A/B may mediate the critical cues for maintaining the differentiation of mammary epithelium. In addition, present data suggest that activation of STAT5A/B in breast cancer predicts favorable clinical outcome. The dual nature of STAT5A/B action in breast cancer makes the therapeutic use of STAT5 A/B more complex.

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“…Subsequently, STAT5 or related proteins were found to be activated by a wide range of cytokines, including growth hormone, IL-3, IL-5, granulocyte/macrophage-CSF, G-CSF, thrombopoietin, erythropoietin, IL-2, IL-4, IL-7, IL-13, IL-15, INF-␥, epidermal growth factor, and CSF-1 (3,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). The presence of two STAT5 genes and an initial lack of suitable specific antibodies created some difficulties in the interpretation of the results.…”

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Formation of STAT5-containing DNA Binding Complexes in Response to Colony-stimulating Factor-1 and Platelet-derived Growth Factor

Novak

Mui

Miyajima

et al. 1996

Journal of Biological Chemistry

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Colony-stimulating factor (CSF-1) activates several members belonging to the STAT (signal transducers and activators of transcription) family of transcription factors. We investigated the DNA binding complexes activated by CSF-1 in several cell lines and compared them with complexes activated by platelet-derived growth factor and interleukin 3. Our results indicate that the SIF-A complex activated by CSF-1 and platelet-derived growth factor may contain STAT3/STAT5 heterodimers binding to the high affinity SIF binding site, m67. In addition, both growth factors activate one or several STAT5-containing protein complexes binding to the prolactin-inducible element, PIE. The formation of these complexes was cell type and growth factor specific. Interleukin 3 activated only PIE binding complexes containing STAT5A and STAT5B and did not activate m67 binding complexes. It appears, therefore, that STAT5 cannot bind to m67 as a homodimer, but it can bind if it is dimerized with STAT3, whereas it can bind to the PIE element without being either complexed with STAT3 or any other known STAT protein, possibly as a homodimer or as STAT5A/STAT5B heterodimer. However, in addition, STAT5 may heterodimerize with other proteins and form novel PIE binding complexes.Over the past several years, a new group of transcription factors has been characterized and cloned (reviewed in Ref. 1). The first members of this family of transcription factors, known as STAT 1 proteins (signal transducers and activators of transcription) were identified as the factors mediating the response to IFN-␣ (2). Subsequently, it has been shown that a wide range of cytokines and growth factors lead to the activation of members of the STAT family. Thus far, six members of the family have been cloned. The STAT5 gene is the only one which has been duplicated (3). The levels of amino acid sequence identity between the different members of the STAT family range between about 50 and 18% (4). However, all known STAT proteins share several features, one SH2 and one SH3-like domain and one C-terminal tyrosine residue, which is phosphorylated upon activation. In addition, several of the STAT proteins require the phosphorylation of a C-terminal serine, located within a well conserved mitogen-activated protein kinase phosphorylation site, for DNA binding, and/or transactivation capacity (5-8). The mitogen-activated protein kinase phosphorylation site is present in STAT1, STAT3, and STAT4; however, the biological requirement for serine phosphorylation has, thus far, only been demonstrated for STAT1 and STAT3 (6).Binding of the STAT proteins to specific DNA sequences on the promoter of regulated genes requires prior dimerization, involving binding of a C-terminal phosphotyrosine of one STAT protein to the SH2 domain of the other. The formation of heterodimeric complexes has been observed, such as STAT1/ STAT2 binding to the interferon-␣/␤ response element via p48 (9), and STAT1/STAT3 binding to the sis-inducible element (SIE) (10). The composition of these complexes has bee...

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Colony‐stimulating factors and interferon‐γ activate a protein related to MGF‐Stat 5 to cause formation of the differentiation‐induced factor in myeloid cells

Cited by 41 publications

References 37 publications

Differentiation-Regulated Serine Phosphorylation of STAT1 Promotes GAF Activation in Macrophages

Differentiation-Regulated Serine Phosphorylation of STAT1 Promotes GAF Activation in Macrophages

Signal transducer and activator of transcription 5A/B in prostate and breast cancers

Formation of STAT5-containing DNA Binding Complexes in Response to Colony-stimulating Factor-1 and Platelet-derived Growth Factor

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