Browsing by Subject "transcription factor"

Now showing 1 - 6 of 6
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    Death-associated Protein Kinase-1 Expression and Autophagy in Chronic Lymphocytic Leukemia Are Dependent on Activating Transcription Factor-6 and CCAAT/Enhancer-binding Protein-β
    (American Society for Biochemistry and Molecular Biology, 2016-10-14) Gade, Padmaja; Kimball, Amy S.; DiNardo, Angela C.; Gangwal, Priyamvada; Ross, Douglas D.; Boswell, H. Scott; Keay, Susan K.; Kalvakolanu, Dhananjaya V.; Medicine, School of Medicine
    Expression of DAPK1, a critical regulator of autophagy and apoptosis, is lost in a wide variety of tumors, although the mechanisms are unclear. A transcription factor complex consisting of ATF6 (an endoplasmic reticulum-resident factor) and C/EBP-β is required for the IFN-γ-induced expression of DAPK1. IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-β are obligatory for the formation of this transcriptional complex. We report that defects in this pathway fail to control growth of chronic lymphocytic leukemia (CLL). Consistent with these observations, IFN-γ and chemotherapeutics failed to activate autophagy in CLL patient samples lacking ATF6 and/or C/EBP-β. Together, these results identify a molecular basis for the loss of DAPK1 expression in CLL.
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    The Ethylene Signaling Pathway Negatively Impacts CBF/DREB-Regulated Cold Response in Soybean (Glycine max)
    (Frontiers, 2019) Robison, Jennifer D.; Yamasaki, Yuji; Randall, Stephen K.; Biology, School of Science
    During cold stress, soybean CBF/DREB1 transcript levels increase rapidly; however, expected downstream targets appear unresponsive. Here we asked whether the ethylene signaling pathway, which is enhanced in the cold can negatively regulate the soybean CBF/DREB1 cold responsive pathway; thus contributing to the relatively poor cold tolerance of soybean. Inhibition of the ethylene signaling pathway resulted in a significant increase in GmDREB1A;1 and GmDREB1A;2 transcripts, while stimulation led to decreased GmDREB1A;1 and GmDREB1B;1 transcripts. A cold responsive reporter construct (AtRD29Aprom::GFP/GUS), as well as predicted downstream targets of soybean CBF/DREB1 [ Glyma.12g015100 (ADH), Glyma.14g212200 (ubiquitin ligase), Glyma.05g186700 (AP2), and Glyma.19g014600 (CYP)] were impacted by the modulation of the ethylene signaling pathway. Photosynthetic parameters were affected by ethylene pathway stimulation, but only at control temperatures. Freezing tolerance (as measured by electrolyte leakage), free proline, and MDA; in both acclimated and non-acclimated plants were increased by silver nitrate but not by other ethylene pathway inhibitors. This work provides evidence that the ethylene signaling pathway, possibly through the action of EIN3, transcriptionally inhibits the CBF/DREB1 pathway in soybean.
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    regSNPs-ASB: A Computational Framework for Identifying Allele-Specific Transcription Factor Binding From ATAC-seq Data
    (Frontiers, 2020-07-29) Xu, Siwen; Feng, Weixing; Lu, Zixiao; Yu, Christina Y.; Shao, Wei; Nakshatri, Harikrishna; Reiter, Jill L.; Gao, Hongyu; Chu, Xiaona; Wang, Yue; Liu, Yunlong; Medical and Molecular Genetics, School of Medicine
    Expression quantitative trait loci (eQTL) analysis is useful for identifying genetic variants correlated with gene expression, however, it cannot distinguish between causal and nearby non-functional variants. Because the majority of disease-associated SNPs are located in regulatory regions, they can impact allele-specific binding (ASB) of transcription factors and result in differential expression of the target gene alleles. In this study, our aim was to identify functional single-nucleotide polymorphisms (SNPs) that alter transcriptional regulation and thus, potentially impact cellular function. Here, we present regSNPs-ASB, a generalized linear model-based approach to identify regulatory SNPs that are located in transcription factor binding sites. The input for this model includes ATAC-seq (assay for transposase-accessible chromatin with high-throughput sequencing) raw read counts from heterozygous loci, where differential transposase-cleavage patterns between two alleles indicate preferential transcription factor binding to one of the alleles. Using regSNPs-ASB, we identified 53 regulatory SNPs in human MCF-7 breast cancer cells and 125 regulatory SNPs in human mesenchymal stem cells (MSC). By integrating the regSNPs-ASB output with RNA-seq experimental data and publicly available chromatin interaction data from MCF-7 cells, we found that these 53 regulatory SNPs were associated with 74 potential target genes and that 32 (43%) of these genes showed significant allele-specific expression. By comparing all of the MCF-7 and MSC regulatory SNPs to the eQTLs in the Genome-Tissue Expression (GTEx) Project database, we found that 30% (16/53) of the regulatory SNPs in MCF-7 and 43% (52/122) of the regulatory SNPs in MSC were also in eQTL regions. The enrichment of regulatory SNPs in eQTLs indicated that many of them are likely responsible for allelic differences in gene expression (chi-square test, p-value < 0.01). In summary, we conclude that regSNPs-ASB is a useful tool for identifying causal variants from ATAC-seq data. This new computational tool will enable efficient prioritization of genetic variants identified as eQTL for further studies to validate their causal regulatory function. Ultimately, identifying causal genetic variants will further our understanding of the underlying molecular mechanisms of disease and the eventual development of potential therapeutic targets.
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    Repression of transforming-growth-factor-beta-mediated transcription by nuclear factor kappaB.
    (Portland Press, 2000-06-15) Nagarajan, R P; Chen, F; Li, W; Vig, E; Harrington, M A; Nakshatri, H; Chen, Y
    Activation of transforming growth factor-beta (TGF-beta) and activin receptors leads to phosphorylation of Sma- and Mad-related protein 2 (Smad2) and Smad3, which function as transcription factors to regulate gene expression. Smad7 is a regulatory protein which is able to inhibit TGF-beta and activin signalling in a negative-feedback loop, mediated by a direct regulation by Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. Interestingly, we found that the Smad7 promoter was also regulated by nuclear factor kappaB (NF-kappaB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-kappaB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IkappaB, an inhibitor of NF-kappaB. In addition, the inhibitory activity of p65 was observed in a minimal promoter that contained only the Smad7 SBE and a TATA box, without any consensus NF-kappaB binding site. This inhibitory effect appeared to be common to other TGF-beta- and activin-responsive promoters, since p65 also inhibited the forkhead-activin-signal-transducer-2-mediated activation of a Xenopus Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 promoter. Activation of endogenous NF-kappaB by tumour necrosis factor-alpha (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-alpha was able to inhibit TGF-beta- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription co-activator p300 could abrogate the inhibitory effect of NF-kappaB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-kappaB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators.
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    Th9 immunodeficiency in Hyper IgE syndrome patients
    (Elsevier, 2018) Olson, Matthew R.; Kaplan, Mark H.; Pediatrics, School of Medicine
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    Weighted gene co-expression network analysis of colorectal patients to identify right drug-right target for potent efficacy of targeted therapy
    (2017-12-10) Tripathi, Anamika; Pradhan, Meeta; Wu, Huanmei
    Colon rectal cancer (CRC) is one of the most common cancers worldwide. It is characterized by the successive accumulation of mutations in genes controlling epithelial cell growth and differentiation leading to genomic in-stability. This results in the activation of proto-oncogene(K-ras), loss of tumor suppressor gene activity and ab-normality in DNA repair genes. Targeted therapy is a new generation of cancer treatment in which drugs attack targets which are specific for the cancer cell and are critical for its survival or for its malignant behavior. Survival of metastatic CRC patients has approximately doubled due to the development of new combinations of stan-dard chemotherapy, and the innovative targeted therapies, such as monoclonal antibodies against epidermal growth factor receptor (EGFR) or monoclonal antibodies against vascular endothelial growth factor (VEGFR).The study is to exhibit the need for right drug-right target and provides a proof of principle for potent efficacy of molecular targeted therapy for CRC. We have performed the weighted gene co-expression network analysis for three different patient cohort treated with different targeted therapy drugs. The results demonstrates the variation across different treatment regime in context of transcription factor networks. New significant tran-scription factors have been identified as potential biomarker for CRC cancer including EP300, STAT6, ATF3, ELK1, HNF4A, JUN, TAF1, IRF1, TP53, ELF1 and YY1. The results provides guidance for future omic study on CRC and additional validation work for potent biomarker for CRC.