Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes

Signal transducer and activator of transcription (STAT) proteins, and in particular STAT3, have been established as heavily implicated in cancer. Recently, the involvement of STAT5 signalling in the pathology of cancer has been shown to be of increasing importance. STAT5 plays a crucial role in the development of the mammary gland and the homeostasis of the immune system. However, in various cancers, aberrant STAT5 signalling promotes the expression of target genes, such as cyclin D, Bcl-2 and MMP-2, that result in increased cell proliferation, survival and metastasis. To target constitutive STAT5 signalling in cancers, there are several STAT5 inhibitors that can prevent STAT5 phosphorylation, dimerisation, or its transcriptional activity. Tyrosine kinase inhibitors (TKIs) that target molecules upstream of STAT5 could also be utilised. Consequently, since STAT5 contributes to tumour aggressiveness and cancer progression, inhibiting STAT5 constitutive activation in cancers that rely on its signalling makes for a promising targeted treatment option.

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Co-activator SRC-1 is dispensable for transcriptional control by STAT3

Biochemical Journal ◽

10.1042/bj20081989 ◽

2009 ◽

Vol 420 (1) ◽

pp. 123-132 ◽

Cited By ~ 6

Author(s):

Helena Cvijic ◽

Kay Bauer ◽

Dennis Löffler ◽

Gabriele Pfeifer ◽

Conny Blumert ◽

...

Keyword(s):

Transcriptional Control ◽

Target Genes ◽

Binding Protein ◽

Myeloma Cell ◽

Camp Response Element Binding ◽

Signal Transducer ◽

Il Interleukin ◽

Element Binding Protein ◽

Induced Apoptosis ◽

Microarray Expression

SRC (steroid receptor co-activator)-1 has been reported to interact with and to be an essential co-activator for several members of the STAT (signal transducer and activator of transcription) family, including STAT3, the major signal transducer of IL (interleukin)-6. We addressed the question of whether SRC-1 is crucial for IL-6- and STAT3-mediated physiological responses such as myeloma cell survival and acute-phase protein induction. In fact, silencing of SRC-1 by RNA interference rapidly induced apoptosis in IL-6-dependent INA-6 human myeloma cells, comparable with what was observed upon silencing of STAT3. Using chromatin immunoprecipitation at STAT3 target regions of various genes, however, we observed constitutive binding of SRC-1 that decreased when INA-6 cells were treated with IL-6. The same held true for STAT3 target genes analysed in HepG2 human hepatocellular carcinoma cells. SRC-1-knockdown studies demonstrated that STAT3-controlled promoters require neither SRC-1 nor the other p160 family members SRC-2 or SRC-3 in HepG2 cells. Furthermore, microarray expression profiling demonstrated that the responsiveness of IL-6 target genes is not affected by SRC-1 silencing. In contrast, co-activators of the CBP [CREB (cAMP-response element-binding protein)-binding protein]/p300 family proved functionally important for the transactivation potential of STAT3 and bound inducibly to STAT3 target regions. This recruitment did not depend on the presence of SRC-1. Altogether, this suggests that functional impairment of STAT3 is not involved in the induction of myeloma cell apoptosis by SRC-1 silencing. We therefore conclude that STAT3 transactivates its target genes by the recruitment of CBP/p300 co-activators and that this process generally does not require the contribution of SRC-1.

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Differential regulation of NF-kB and IRF target genes as they relate to fatigue in patients with head and neck cancer

Brain Behavior and Immunity ◽

10.1016/j.bbi.2018.09.013 ◽

2018 ◽

Vol 74 ◽

pp. 291-295 ◽

Cited By ~ 4

Author(s):

Canhua Xiao ◽

Jonathan J. Beitler ◽

Kristin A. Higgins ◽

Evanthia C. Wommack ◽

Nabil F. Saba ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Target Genes ◽

Differential Regulation

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Physiological and Receptor-selective Retinoids Modulate Interferon γ Signaling by Increasing the Expression, Nuclear Localization, and Functional Activity of Interferon Regulatory Factor-1

Journal of Biological Chemistry ◽

10.1074/jbc.m505749200 ◽

2005 ◽

Vol 280 (43) ◽

pp. 36228-36236 ◽

Cited By ~ 20

Author(s):

Xin M. Luo ◽

A. Catharine Ross

Keyword(s):

Retinoic Acid ◽

Nuclear Localization ◽

Target Genes ◽

Interferon Γ ◽

Epithelial Cell Line ◽

Transcriptional Level ◽

Signal Transducer ◽

Regulatory Factor

Synergistic actions between all-trans-retinoic acid (atRA) and interferon γ (IFNγ) on modulation of cellular functions have been reported both in vitro and in vivo. However, the mechanism of atRA-mediated regulation of IFNγ signaling is poorly understood. In this study, we have used the human lung epithelial cell line A549 to examine the effect of atRA on IFNγ-induced expression of IFN regulatory factor-1 (IRF-1), an important transcription factor involved in cell growth and apoptosis, differentiation, and antiviral and antibacterial immune responses. At least 4 h of pretreatment with atRA followed by suboptimal concentrations of IFNγ induced a faster, higher, and more stable expression of IRF-1 than IFNγ alone. Actinomycin D completely blocked the induction of IRF-1 by the combination, suggesting regulation at the transcriptional level. Further, we found that activation of signal transducer and activator of transcription-1 was induced more dramatically by atRA and IFNγ than by IFNγ alone. Expression of IFNγ receptor-1 on the cell surface was also increased upon atRA pretreatment. Experiments using receptor-selective retinoids revealed that ligands for retinoic acid receptor-α (RARα), including atRA, 9-cis-retinoic acid, and Am580, sequentially increased the levels of IFNγ receptor-1, activated signal transducer and activator of transcription-1, and IRF-1 and that an RARα antagonist was able to inhibit the effects of atRA and Am580. In addition, atRA pretreatment affected the transcriptional functions of IFNγ-induced IRF-1, increasing its nuclear localization and DNA binding activity as well as the transcript levels of IRF-1 target genes. These results suggest that atRA, an RARα ligand, regulates IFNγ-induced IRF-1 by affecting multiple components of the IFNγ signaling pathway, from the plasma membrane to the nuclear transcription factors.

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MiR-146a/b: a family with shared seeds and different roots

Physiological Genomics ◽

10.1152/physiolgenomics.00133.2016 ◽

2017 ◽

Vol 49 (4) ◽

pp. 243-252 ◽

Cited By ~ 48

Author(s):

Mark R. Paterson ◽

Alison J. Kriegel

Keyword(s):

Target Genes ◽

Family Members ◽

Differential Regulation ◽

Seed Region ◽

Small Noncoding Rnas ◽

Specific Effects ◽

Exciting Potential ◽

Health And Disease ◽

Experimental Approaches ◽

Functional Relevance

MicroRNAs are small, noncoding, RNAs known for their powerful modulation of molecular processes, making them a major focus for studying pathological mechanisms. The human miR-146 family of microRNAs consists of two member genes, MIR146A and MIR146B. These two microRNAs are located on different chromosomes and exhibit differential regulation in many cases. However, they are nearly identical in sequence, sharing a seed region, and are thus predicted to target the same set of genes. A large proportion of the microRNA (miR)-146 literature focuses on its role in regulating the innate immune response in the context of various pathologies by modulating two widely studied target genes in the toll-like receptor signaling cascade. A growing subset of the literature reports a role of miR-146 in cardiovascular and renal disease, and data suggest there is exciting potential for miR-146 as a diagnostic and therapeutic target. Nevertheless, the published literature is confounded by unclear and imprecise language concerning the specific effects of the two miR-146 family members. The present review will compare the genomic origin and regulation of miR-146a and miR-146b, discuss some approaches to overcome analytical and experimental challenges, and summarize findings in major areas of miR-146 research. Moving forward, careful evaluation of miR-146a/b specificity in analytical and experimental approaches will aid researchers in elucidating the functional relevance of differential regulation of the miR-146 family members in health and disease.

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Inhibition of Signal Transducer and Activator of Transcription 6 Activity in the Hodgkin Lymphoma Cell Line L1236 Induces Growth Inhibition and Apoptosis.

Blood ◽

10.1182/blood.v108.11.4593.4593 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4593-4593

Author(s):

Cheng Liu ◽

Margareta Andersson ◽

Dawei Xu ◽

Hans-Erik Claesson ◽

Magnus Bjorkholm ◽

...

Keyword(s):

Growth Inhibition ◽

Cell Line ◽

Hodgkin Lymphoma ◽

Target Genes ◽

Signal Transducer ◽

Autocrine Growth ◽

Regulated Expression ◽

Hodgkin Lymphoma Cell ◽

Interfering Rna

Abstract Signal transducer and activator of transcription 6 (STAT6) plays a central role in interleukin (IL)-4 and -13 signaling. Upon binding of the cognate receptors by these cytokines, STAT6 becomes phosphorylated by Jak family kinases and subsequently translocates to the nucleus where transcription of its target genes is regulated. Expression of IL-13 and its receptor are common features of Hodgkin lymphoma (HL) tumor cells, the so-called Hodgkin Reed-Sternberg (H-RS) cells, in which this cytokine has been shown to act as an autocrine growth factor. Consequently, constitutively phosphorylated STAT6 with a nuclear localization is a common and distinctive feature of H-RS cells in classical HL. We knocked down STAT6 expression in the HL cell line L1236 with small interfering RNA (siRNA) and found that inhibition of STAT6 activity results in cell growth inhibition, decreased viability and increased apoptosis. The results depict a central role of STAT6 in the growth of H-RS cells and indicate that STAT6 could be a potential target for therapeutic intervention in HL. Moreover, in order to identify the target genes of this transcription factor in H-RS cells, a combined approach of RNA interference and microarray is performed and the results will be presented.

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Differential Regulation of NF-κB by Elongation Factors Is Determined by Core Promoter Type

Molecular and Cellular Biology ◽

10.1128/mcb.00586-07 ◽

2007 ◽

Vol 27 (14) ◽

pp. 5246-5259 ◽

Cited By ~ 51

Author(s):

Liat Amir-Zilberstein ◽

Elena Ainbinder ◽

Leanne Toube ◽

Yuki Yamaguchi ◽

Hiroshi Handa ◽

...

Keyword(s):

Immune Response ◽

Transcription Factors ◽

Rna Polymerase Ii ◽

Target Genes ◽

Core Promoter ◽

Underlying Mechanism ◽

Differential Regulation ◽

Elongation Factors ◽

The Core ◽

Regulatory Link

ABSTRACT NF-κB transcription factors activate genes important for immune response, inflammation, and cell survival. P-TEFb and DSIF, which are positive and negative transcription elongation factors, respectively, both regulate NF-κB-induced transcription, but the mechanism underlying their recruitment to NF-κB target genes is unknown. We show here that upon induction of NF-κB, a subset of target genes is regulated differentially by either P-TEFb or DSIF. The regulation of these genes and their occupancy by these elongation factors are dependent on the NF-κB enhancer and the core promoter type. Converting a TATA-less promoter to a TATA promoter switches the regulation of NF-κB from DSIF to P-TEFb. Accumulation or displacement of DSIF and P-TEFb is dictated by the formation of distinct initiation complexes (TFIID dependent or independent) on the two types of core promoter. The underlying mechanism for the dissociation of DSIF from TATA promoters upon NF-κB activation involves the phosphorylation of RNA polymerase II by P-TEFb. The results highlight a regulatory link between the initiation and the elongation phases of the transcription reaction and broaden our comprehension of the NF-κB pathway.

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Increased prolyl 4-hydroxylase expression and differential regulation of hypoxia-inducible factors in the aged rat brain

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90829.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. R158-R165 ◽

Cited By ~ 30

Author(s):

Obinna I. Ndubuizu ◽

Juan C. Chavez ◽

Joseph C. LaManna

Keyword(s):

Cerebral Cortex ◽

Rat Brain ◽

Mammalian Cells ◽

Target Genes ◽

Differential Regulation ◽

Mrna Levels ◽

Hypoxia Inducible Factors ◽

Aged Rat ◽

Fischer 344 ◽

Fischer 344 Rat

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that mediate the adaptive response of mammalian cells and tissues to changes in tissue oxygenation. In the present study, we show an age-dependent decline in cortical HIF-1α accumulation and activation of HIF target genes in response to hypoxia. This inducible response is significantly attenuated in the cerebral cortex of 18-mo-old Fischer 344 rat yet virtually absent in the cerebral cortex of 24-mo-old Fischer 344 rat. This attenuated HIF-1α response had no effect on mRNA upregulation of HIF-independent genes in the aged cortex. We have provided evidence that this absent HIF-1α response is directly correlated with an increase in the expression of the HIF regulatory enzyme, prolyl 4-hydroxylase (PHD). In addition, our study shows that cortical HIF-2α expression in senescent normoxic controls is also significantly greater than that of younger normoxic controls, despite no difference in HIF-2α mRNA levels. The posttranslational regulation of HIF-2α under normoxic conditions seems to be attenuated in the aged rat brain, which is an in vivo demonstration of differential regulation of HIF-1α and HIF-2α.

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization

10.1101/437160 ◽

2018 ◽

Author(s):

Kyuho Kang ◽

Sung Ho Park ◽

Keunsoo Kang ◽

Lionel B. Ivashkiv

Keyword(s):

Histone Acetylation ◽

Metabolic Pathways ◽

Target Genes ◽

Macrophage Polarization ◽

Differential Regulation ◽

Inflammatory Genes ◽

Synergistic Activation ◽

M1 Polarization ◽

Combined Action ◽

Ifn Γ

AbstractComplete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.

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The extracellular domain of the human interferon gamma receptor interacts with a species-specific signal transducer

Molecular and Cellular Biology ◽

10.1128/mcb.11.12.5860-5866.1991 ◽

1991 ◽

Vol 11 (12) ◽

pp. 5860-5866

Author(s):

V C Gibbs ◽

S R Williams ◽

P W Gray ◽

R D Schreiber ◽

D Pennica ◽

...

Keyword(s):

Human Chromosome ◽

Cell Lines ◽

Interferon Gamma ◽

Extracellular Domain ◽

Chromosome 21 ◽

Signal Transducer ◽

Ifn Gamma ◽

Human Chromosome 21 ◽

Gamma Receptor ◽

Species Specific

At least two species-specific gene products are required for signal transduction by interferon gamma (IFN-gamma). The first is the IFN-gamma receptor, which binds ligand with high affinity in a species-specific manner. The second is an undetermined species-specific signal transducer(s). To determine whether the human IFN-gamma receptor (hIFN-gamma R) interacts directly with this signal transducer(s) and, if so, with what functional domain(s), we constructed expression vectors for the hIFN-gamma R and three hybrid human-murine IFN-gamma receptors. The hybrid receptors contained the extracellular, human IFN-gamma (hIFN-gamma) binding domain of the hIFN-gamma R, either the human or murine transmembrane domain, and either the human or murine intracellular domain. The vectors encoding these receptors were stably transfected into two mouse cell lines, one of which (SCC-16-5) contains a single copy of human chromosome 21. The resulting cell lines were treated with hIFN-gamma, and murine major histocompatibility complex class I antigen expression was analyzed by immunofluorescence flow cytometry. All transfected cell lines lacking human chromosome 21 remained insensitive to hIFN-gamma. However, all four of the IFN-gamma receptors were able to signal when expressed in the cell line containing human chromosome 21. We conclude that the extracellular domain of the IFN-gamma receptor is involved not only in the species specificity of IFN-gamma binding but also in signalling through interaction with an as yet unidentified species-specific factor(s) encoded by a gene(s) on human chromosome 21.

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