scholarly journals Bromodomain and Extraterminal Inhibition by JQ1 Produces Divergent Transcriptional Regulation of Suppressors of Cytokine Signaling Genes in Adipocytes

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Paula Mota de Sá ◽  
Allison J Richard ◽  
Jacqueline M Stephens
Keyword(s):  
Transcriptional Regulation ◽  
Transcriptional Activation ◽  
Messenger Rna ◽  
Target Genes ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Coding Region ◽  
Pol Ii ◽  
Stat Signaling ◽  
Suppressors Of Cytokine Signaling

Abstract The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway has cell-specific functions. Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of JAK-STAT signaling. STAT5 plays a significant role in adipocyte development and function, and bromodomain and extraterminal (BET) proteins may be involved in STAT5 transcriptional activity. We treated 3T3-L1 adipocytes with the BET inhibitor JQ1 and observed that growth hormone (GH)-induced expression of 2 STAT5 target genes from the SOCS family, Socs3 and Cish, were inversely regulated (increased and decreased, respectively) by BET inhibition. Chromatin immunoprecipitation analyses revealed that changes in STAT5 binding did not correlate with gene expression changes. GH promoted the recruitment of the BET protein BRD2 to the Cish, but not Socs3, promoter. JQ1 treatment ablated this effect as well as the GH-induced binding of ribonucleic acid polymerase II (RNA Pol II) to the Cish transcription start site. BRD2 knockdown also suppressed GH induction of Cish, further supporting the role of BRD2 in Cish transcriptional activation. In contrast, JQ1 increased the binding of activated Pol II to the Socs3 coding region, suggesting enhanced messenger RNA (mRNA) elongation. Our finding that JQ1 transiently reduced the interaction between the positive transcription elongation factor (P-TEFb) and its inhibitor hexamethylene bis-acetamide inducible 1 (HEXIM1) is consistent with a previously described off-target effect of JQ1, whereby P-TEFb becomes more available to be recruited by genes that do not depend on BET proteins for activating transcription. These results demonstrate substantially different transcriptional regulation of Socs3 and Cish and suggest distinct roles in adipocytes for these 2 closely related proteins.

Atomistic insight into the inhibition mechanisms of suppressors of cytokine signaling on Janus kinase

2019 ◽  
Vol 21 (24) ◽  
pp. 12905-12915 ◽  
Author(s):  
Yaru Wei ◽  
Zhiyang Zhang ◽  
Nai She ◽  
Xin Chen ◽  
Yuan Zhao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Negative Feedback ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Jak Kinase ◽  
Stat Signaling ◽  
Suppressors Of Cytokine Signaling ◽  
Insight Into

Suppressors of cytokine signaling (SOCS) act as negative feedback regulators of the Janus kinase/signal transducer (JAK–STAT) signaling pathway by inhibiting the activity of JAK kinase.

Abstract 19: Microrna-19b Enhances Cardiac Cell Survival After Ischemic Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Bas Molenaar ◽  
Charlotte Demkes ◽  
Hester Ruiter, de ◽  
Danielle Versteeg ◽  
Monika Gladka-de Vries ◽  
...  
Keyword(s):  
Target Genes ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Janus Kinase ◽  
Luciferase Reporter ◽  
Cytokine Signaling ◽  
Therapeutic Benefits ◽  
Stat Signaling ◽  
Cardiomyocyte Survival

Ischemia/reperfusion (I/R) injury in cardiac tissue results in substantial loss of cardiomyocytes, leading to a functional decline. The release of several cytokines increases cardiomyocyte survival after ischemic injury by activating the janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway. However, this pathway is inhibited by Suppressor of cytokine signaling (SOCS)1 and SOCS3, which act as endogenous negative regulators of cardiomyocyte survival by blocking JAK activity. MicroRNAs (miRNAs) are small, non-coding RNAs that can repress gene expression by binding to recognition sequences within target genes. In a bioinformatic screen, we identified conserved binding sites in SOCS1 and 3 for miR-19b. Using a luciferase reporter assay, we were able to confirm direct binding of miR-19b to the 3’-UTR of both SOCS1 and 3 in vitro . In addition, we found that miR-19b downregulates SOCS1 in cardiac-like cells and isolated neonatal cardiomyocytes. In vivo , we observed a downregulation of miR-19b in both rodent and human cardiac tissues after ischemic injury, which corresponds to an upregulation of both SOCS1 and 3. Since inhibition of SOCS1 and 3 could enhance cardiac JAK-STAT signaling, miRNA-based inhibition could lead to an increase in cardiomyocyte survival. Here we show that cardiomyocyte-specific overexpression of miR-19b lowers SOCS1 and SOCS3 expression and enhances JAK-STAT signaling during ischemia reperfusion, which corresponds to a decrease in the pro-apoptotic proteins Bad, Bax and P53. Additional genes that are decreased by miR-19b during ischemic injury are Rnf11 and TNFAIP3, both repressors NF-kB signaling. To further explore the cardioprotective effects of miR-19b, we are currently investigating the therapeutic benefits of administering synthetic miR-19b mimics through intracardiac injection after I/R injury in mice. Our study indicates a conserved mechanism by which miR-19b targets both SOCS1 and 3 and to increase the activation of JAK/STAT signaling to decrease cardiomyocyte apoptosis. Administration of miR-19b mimics might be of therapeutic interest to enhance cardiomyocyte cells survival and preserve heart function in the setting of ischemic injury.

scholarly journals In vitro expression of long and short ovine prolactin receptors: activation of Jak2/STAT5 pathway is not sufficient to account for prolactin signal transduction to the ovine beta-lactoglobulin gene promoter

1999 ◽  
Vol 23 (2) ◽  
pp. 125-136 ◽  
Author(s):  
C Bignon ◽  
N Daniel ◽  
L Belair ◽  
J Djiane
Keyword(s):  
Tyrosine Phosphorylation ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Gene Promoter ◽  
Janus Kinase ◽  
Prolactin Receptors ◽  
Milk Protein Gene ◽  
Prolactin Signaling ◽  
Beta Lactoglobulin

The recent finding that sheep had long (l-oPRLR) and short (s-oPRLR) prolactin receptors provided new tools to further explore prolactin signaling to target genes. Here we used CHO cells transfected with l-oPRLR or s-oPRLR cDNAs to compare the activation of known key steps of prolactin signaling by the two receptors. We found that prolactin stimulated l-oPRLR tyrosine phosphorylation, although it lacked the last tyrosine residue found in other long prolactin receptors. In addition, l-oPRLR and s-oPRLR both responded to prolactin stimulation by (1) Janus kinase 2 (Jak2) tyrosine phosphorylation, (2) DNA-binding activation of signal transducer and activator of transcription 5 (STAT5), (3) stimulation of transcription from a promoter made of six repeats of STAT5-responsive sequence. However, although it contains STAT5-binding consensus sequences, the ovine beta-lactoglobulin promoter (-4000 to +40) was transactivated by l-oPRLR, but not by s-oPRLR. Taken together, our results indicate that activation of Jak2/STAT5 pathway alone is not sufficient to account for prolactin-induced transcription of this milk protein gene, and that sequences of its promoter, other than STAT5-specific sequences, account for the opposite transcriptional activation capabilities of l-oPRLR and s-oPRLR.

scholarly journals Molecular Cloning and Expression Analysis of Three Suppressors of Cytokine Signaling Genes (SOCS5, SOCS6, SOCS7) in the Mealworm Beetle Tenebrio molitor

Insects ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 76 ◽  
Author(s):  
Bharat Patnaik ◽  
Bo Kim ◽  
Yong Jo ◽  
In Bang
Keyword(s):  
Functional Characterization ◽  
Tenebrio Molitor ◽  
Janus Kinase ◽  
Cloning And Expression ◽  
Cytokine Signaling ◽  
Type I ◽  
Growth Factor Signaling ◽  
Expression Levels ◽  
Mealworm Beetle ◽  
Suppressors Of Cytokine Signaling

Suppressors of cytokine signaling (SOCS) influence cytokine and growth factor signaling by negatively regulating the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway to maintain homeostasis during immune responses. However, functional characterization of SOCS family members in invertebrates is limited. Here, we identified and evaluated three SOCS genes (type I sub-family) in the mealworm beetle Tenebrio molitor. The full-length open reading frames (ORFs) of TmSOCS5, TmSOCS6, and TmSOCS7 comprised of 1389, 897, and 1458 nucleotides, encoding polypeptides of 462, 297, and 485 amino acids, respectively. The SH2 and SOCS box domains of the TmSOCS C-terminal region were highly conserved. Phylogenetic analysis revealed that these SOCS genes were clustered within the type I subfamily that exhibits the highest amino acid identity with Tribolium castaneum SOCS genes. Contrary to TmSOCS7 expression, the expression levels of TmSOCS5 and TmSOCS6 were lower in the larval, pupal, and adult stages. In larvae and adults, the expression levels of TmSOCS5 and TmSOCS6 were highest in the hemocytes and ovaries, respectively. SOCS transcripts were also highly upregulated in the hemocytes of T. molitor larvae within 3–6 h post-infection with the fungus Candida albicans. Collectively, these results provide valuable information regarding the involvement of TmSOCS type-I subfamily in the host immune response of insects.

scholarly journals Pausing sites of RNA polymerase II on actively transcribed genes are enriched in DNA double-stranded breaks

2020 ◽  
Vol 295 (12) ◽  
pp. 3990-4000 ◽  
Author(s):  
Sandeep Singh ◽  
Karol Szlachta ◽  
Arkadi Manukyan ◽  
Heather M. Raimer ◽  
Manikarna Dinda ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Topoisomerase I ◽  
Cell Types ◽  
Dna Breaks ◽  
Transcription Start ◽  
Pol Ii ◽  
Transcription Start Sites

DNA double-stranded breaks (DSBs) are strongly associated with active transcription, and promoter-proximal pausing of RNA polymerase II (Pol II) is a critical step in transcriptional regulation. Mapping the distribution of DSBs along actively expressed genes and identifying the location of DSBs relative to pausing sites can provide mechanistic insights into transcriptional regulation. Using genome-wide DNA break mapping/sequencing techniques at single-nucleotide resolution in human cells, we found that DSBs are preferentially located around transcription start sites of highly transcribed and paused genes and that Pol II promoter-proximal pausing sites are enriched in DSBs. We observed that DSB frequency at pausing sites increases as the strength of pausing increases, regardless of whether the pausing sites are near or far from annotated transcription start sites. Inhibition of topoisomerase I and II by camptothecin and etoposide treatment, respectively, increased DSBs at the pausing sites as the concentrations of drugs increased, demonstrating the involvement of topoisomerases in DSB generation at the pausing sites. DNA breaks generated by topoisomerases are short-lived because of the religation activity of these enzymes, which these drugs inhibit; therefore, the observation of increased DSBs with increasing drug doses at pausing sites indicated active recruitment of topoisomerases to these sites. Furthermore, the enrichment and locations of DSBs at pausing sites were shared among different cell types, suggesting that Pol II promoter-proximal pausing is a common regulatory mechanism. Our findings support a model in which topoisomerases participate in Pol II promoter-proximal pausing and indicated that DSBs at pausing sites contribute to transcriptional activation.

scholarly journals Long non-coding RNA RP11-468E2.5 curtails colorectal cancer cell proliferation and stimulates apoptosis via the JAK/STAT signaling pathway by targeting STAT5 and STAT6

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Li Jiang ◽  
Xu-Hai Zhao ◽  
Yin-Ling Mao ◽  
Jun-Feng Wang ◽  
Hui-Jun Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Target Genes ◽  
Biological Activities ◽  
Janus Kinase ◽  
Normal Tissues ◽  
Stat Signaling

Abstract Background Long non-coding RNAs (lncRNAs) are tumor-associated biological molecules and have been found to be implicated in the progression of colorectal cancer (CRC). This study aims to examine the effects of lncRNA RP11-468E2.5 and its target genes (STAT5 and STAT6) on the biological activities of CRC cells via the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway. Methods We initially screened the GEO database for differentially expressed lncRNAs related to CRC and then made a prediction of the implicated target genes. Then we collected CRC tissues and adjacent normal tissues from 169 CRC patients. Human CRC HCT116 and SW480 cells were treated with small interference RNA (siRNA) against RP11-468E2.5, AG490 (an inhibitor of the JAK/STAT signaling pathway), or both in combination. Next, we measured the effects of RP11-468E2.5 treatment on cellular activities such as cell viability, cycle distribution and cell apoptosis, and studied interactions among RP11-468E2.5, STAT5/STAT6, and the JAK/STAT signaling pathway. Finally, an in vivo tumor formation assay was performed to observe the effect of RP11-468E2.5 on tumor growth. Results The CRC-related gene microarray data showed low expression of RP11-468E2.5 in CRC surgical specimens. However, RP11-468E2.5 was confirmed to target STAT5 and STAT6, which participate in the JAK/STAT signaling pathway. CRC tissues showed lower expression of RP11-468E2.5, higher expression of STAT5, STAT6 and of the cell cycle marker Cyclin D1 (CCND1), compared to the findings in adjacent normal tissues. The treatment of siRNA against RP11-468E2.5 increased expression of JAK2, STAT3, STAT5, STAT6, CCND1 and Bcl-2 along with the extent of STAT3, STAT5 and STAT6 phosphorylation, while lowering expression of P21 and P27. Treatment with AG490 exhibited approximately opposite effects, whereas siRNA against RP11-468E2.5 treatment stimulated CRC cell proliferation and reduced cell apoptosis, while promoting cell cycle entry; AG490 treatment reversed these results. Conclusions Altogether, we conclude that up-regulation of RP11-468E2.5 inhibits the JAK/STAT signaling pathway by targeting STAT5 and STAT6, thereby suppressing cell proliferation and promoting cell apoptosis in CRC.

scholarly journals Suppressors of Cytokine Signaling Regulate Angiotensin II-Activated Janus Kinase-Signal Transducers and Activators of Transcription Pathway in Renal Cells

2005 ◽  
Vol 16 (6) ◽  
pp. 1673-1683 ◽  
Author(s):  
Purificación Hernández-Vargas ◽  
Oscar López-Franco ◽  
Guillermo Sanjuán ◽  
Mónica Rupérez ◽  
Guadalupe Ortiz-Muñoz ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Renal Cells ◽  
Signal Transducers ◽  
Suppressors Of Cytokine Signaling ◽  
Signal Transducers And Activators

A Novel Small-Molecule Approach To Inhibit Jak2 Tyrosine Kinase Signaling.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1556-1556
Author(s):  
Vaibhav Kapuria ◽  
Geoffrey Bartholomeusz ◽  
Ling-Yuan Kong ◽  
William Bornmann ◽  
Zhenghong Peng ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Target Genes ◽  
Jak2 V617f ◽  
Receptor Protein ◽  
Cytokine Signaling ◽  
Growth Factor Signaling ◽  
Intact Cells ◽  
Stat Signaling ◽  
Specific Proteins

Abstract Jak kinases are non-receptor protein tyrosine kinases that play a pivotal role in cytokine/growth factor signaling through phosphorylation of specific proteins such as the Stat molecules. Activated Stats translocate to the nucleus where they mediate transcription of several target genes involved in cell cycle progression and survival (Bcl-xL, cyclin D1, c-myc, survivin. Many tumors have highly activated Stats that are associated with aberrant Jak2 regulation and recent studies have shown that activating mutations in Jak2 (V617F) play a key role in many myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. Jak inhibitors may be useful in treating many diseases with aberrant Jak2/Stat signaling. The most commonly used inhibitor of Jak2 is the tyrphostin AG490, which inhibits Stat3 activation by preventing its tyrosine phosphorylation. However AG490 has limited in vivo efficacy and must be administered at high concentrations (>50 μM) for anti-tumor effects. We describe here a new class of compounds, termed degrasyns, that block Jak2 mediated activation of Stat3 in intact cells at high nM to low μM concentrations. Degrasyns (WP1130/CP2005) did not directly inhibit Jak2 tyrosine kinase activity but suppressed Stat3 activation by reducing the cytoplasmic levels of Jak2. Degrasyn-mediated Jak2 down-regulation was rapid (complete in 2 hrs) and not inhibited by proteasomal, lysosomal, or serine/threonine protease inhibitors. Biochemical studies and confocal microscopy show that degrasyn induces translocation of Jak2 from the plasma membrane/cytosolic fraction into the cytoskeletal fraction and this altered partitioning of Jak2 was associated with loss of cytokine-mediated Stat activation by degrasyn. Jak2 translocation was associated with tyrosine phosphorylation of specific proteins which complex with Jak2. Lyn kinase in the cytoskeletal fraction was highly activated by degrasyn in multiple hematopoetic tumors (multiple myeloma, mantle cell lymphoma, leukemias). Jak2 translocation and Stat inhibition by degrasyn is mechanistically distinct from “classical” Jak2 inhibitors and is not associated with a translocation of other kinases or cytokine signaling molecules in the Jak2 cascade (IL-6R, gp130, Lyn, Btk, Hck, Akt, PI-3K, Erk, Src, Jak1). Degrasyn induces cytoskeletal translocation of both wild-type and mutant (V617F) Jak2 and was associated with induction of apoptosis in HEL cells expressing the Jak2 V617F mutation. These results suggest that degrasyn suppresses Jak/Stat signaling through a unique mechanism involving translocation of Jak2 into a signal transduction incompetent compartment and may be used to investigate a novel form of Stat suppression. Degrasyn may also have anti-tumor effects on cells with aberrant activation of Jak/Stat signaling.

scholarly journals A Global View of Transcriptional Regulation by Nuclear Receptors: Gene Expression, Factor Localization, and DNA Sequence Analysis

2008 ◽  
Vol 6 (1) ◽  
pp. nrs.06005 ◽  
Author(s):  
Miltiadis Kininis ◽  
W. Lee Kraus
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Rna Polymerase Ii ◽  
Nuclear Receptors ◽  
Dna Sequences ◽  
Target Genes ◽  
Large Body ◽  
Pol Ii ◽  
Global View ◽  
Genomic Analyses

Recent genomic analyses of transcription factor binding, histone modification, and gene expression have provided a global view of transcriptional regulation by nuclear receptors (NRs) that complements an existing large body of literature on gene-specific studies. The picture emerging from these genomic studies indicates that NRs bind at promoter-proximal and promoter-distal enhancers in conjunction with other transcription factors (e.g., activator protein-1, Sp1 and FOXA1). This binding promotes the recruitment of coregulators that mediate the posttranslational modification of histones at promoters and enhancers. Ultimately, signaling through liganded NRs stimulates changes in the occupancy of RNA polymerase II (Pol II) or the activation of preloaded Pol II at target promoters. Chromosomal looping and/or Pol II tracking may underlie promoter-enhancer communication. Interestingly, the direct target genes of NR signaling represent a limited subset of all the genes regulated by NR ligands, with the rest being regulated through secondary effects. As suggested by previous gene-specific analyses, NR-mediated outcomes are highly cell type- and promoter-specific, highlighting the complexity of transcriptional regulation by NRs and the value of genomic analyses for identifying commonly shared patterns. Overall, NRs share common themes in their patterns of localization and transcriptional regulation across mammalian genomes. In this review, we provide an overview of recent advances in the understanding of NR-mediated transcription garnered from genomic analyses of gene expression, factor localization, and target DNA sequences.

scholarly journals The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4000
Author(s):  
Esra’a Keewan ◽  
Ksenia Matlawska-Wasowska
Keyword(s):  
Intracellular Signaling ◽  
Cell Communication ◽  
Janus Kinase ◽  
Signaling Cascades ◽  
Cytokine Signaling ◽  
Surface Receptors ◽  
Wide Range ◽  
Stat Signaling ◽  
Leukemia Development

Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.

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