Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fos gene expression

The gastric hormone gastrin and its precursors promote proliferation in several gastrointestinal cell types. Here we show that gastrin induces transcription of cell cycle gene cyclin D1 and protooncogene c- fos in the neuroendocrine pancreatic cell line AR42J and that this gastrin response is inhibited by endogenous inducible cAMP early repressor (ICER). The transcriptional repressor ICER is known to downregulate both its own expression and the expression of other genes containing cAMP-responsive elements (CREs). Using siRNA, we also show that CRE promoter elements are the targets of endogenous ICER in AR42J cells as well as in the neuroendocrine cell line RIN5F. Our results suggest that ICER plays an important role in molecular mechanisms governing gastrin-mediated growth by modulating gastrin's transcriptional activation of growth-related genes. Our finding that ICER modulates pituitary adenylate cyclase-activating polypeptide-activated gene expression also indicates a regulatory effect of ICER in the responses of neuroendocrine cells to peptides other than gastrin.

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MO262THE SINGLE-CELL TRANSCRIPTOMICS OF HUMAN IGA NEPHROPATHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab104.0020 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Yong Zhong ◽

Xiangcheng Xiao

Keyword(s):

Gene Expression ◽

Single Cell ◽

Signaling Pathways ◽

Iga Nephropathy ◽

Molecular Mechanisms ◽

Mesangial Cells ◽

Therapeutic Targets ◽

Cell Types ◽

Receptor Crosstalk ◽

Overt Proteinuria

Abstract Background and Aims The exact molecular mechanisms underlying IgA nephropathy (IgAN) remains incompletely defined. Therefore, it is necessary to further elucidate the mechanism of IgA nephropathy and find novel therapeutic targets. Method Single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from 4 IgAN and 1 control subjects to define the transcriptomic landscape at the single-cell resolution. Unsupervised clustering analysis of kidney specimens was used to identify distinct cell clusters. Differentially expressed genes and potential signaling pathways involved in IgAN were also identified. Results Our analysis identified 14 cell subsets in kidney biopsies from IgAN patients, and analyzed changing gene expression in distinct renal cell types. We found increased mesangial expression of several novel genes including MALAT1, GADD45B, SOX4 and EDIL3, which were related to proliferation and matrix accumulation and have not been reported in IgAN previously. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. Moreover, the receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. Specifically, IgAN with overt proteinuria displayed elevated genes participating in several signaling pathways which may be involved in pathogenesis of progression of IgAN. Conclusion The comprehensive analysis of kidney biopsy specimen demonstrated different gene expression profile, potential pathologic ligand-receptor crosstalk, signaling pathways in human IgAN. These results offer new insight into pathogenesis and identify new therapeutic targets for patients with IgA nephropathy.

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Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

10.1101/2020.02.10.941872 ◽

2020 ◽

Author(s):

Connor Rogerson ◽

Samuel Ogden ◽

Edward Britton ◽

Yeng Ang ◽

Andrew D. Sharrocks ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Molecular Mechanisms ◽

Target Genes ◽

Prognostic Significance ◽

Gene Expression Signature ◽

Chromatin Accessibility ◽

Oesophageal Adenocarcinoma ◽

Cell Cycle Gene ◽

A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

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The ETS-Domain Transcription Factor Elk-1 Regulates COX-2 Gene Expression and Inhibits Glucose-Stimulated Insulin Secretion in the Pancreaticβ-Cell Line INS-1

International Journal of Endocrinology ◽

10.1155/2013/843462 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8

Author(s):

Xiong-Fei Zhang ◽

Yi Zhu ◽

Wen-Biao Liang ◽

Jing-Jing Zhang

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Transcriptional Regulation ◽

Insulin Secretion ◽

Cell Line ◽

Molecular Mechanisms ◽

Cell Function ◽

Cell Dysfunction ◽

Cox 2 ◽

Glucose Stimulated Insulin Secretion

Cyclooxygenase-2 (COX-2) expression is associated with many aspects of physiological and pathological conditions, including pancreaticβ-cell dysfunction. Prostaglandin E2 (PGE2) production, as a consequence of COX-2 gene induction, has been reported to impairβ-cell function. The molecular mechanisms involved in the regulation of COX-2 gene expression are not fully understood. We previously demonstrated that transcription factor Elk-1 significantly upregulated COX-2 gene promoter activity. In this report, we used pancreaticβ-cell line (INS-1) to explore the relationships between Elk-1 and COX-2. We first investigated the effects of Elk-1 on COX-2 transcriptional regulation and expression in INS-1 cells. We thus undertook to study the binding of Elk-1 to its putative binding sites in the COX-2 promoter. We also analysed glucose-stimulated insulin secretion (GSIS) in INS-1 cells that overexpressed Elk-1. Our results demonstrate that Elk-1 efficiently upregulates COX-2 expression at least partly through directly binding to the −82/−69 region of COX-2 promoter. Overexpression of Elk-1 inhibits GSIS in INS-1 cells. These findings will be helpful for better understanding the transcriptional regulation of COX-2 in pancreaticβ-cell. Moreover, Elk-1, the transcriptional regulator of COX-2 expression, will be a potential target for the prevention ofβ-cell dysfunction mediated by PGE2.

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The grapevine R2R3-type MYB transcription factor VdMYB1 positively regulates defense responses by activating the stilbene synthase gene 2 (VdSTS2)

BMC Plant Biology ◽

10.1186/s12870-019-1993-6 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Yihe Yu ◽

Dalong Guo ◽

Guirong Li ◽

Yingjun Yang ◽

Guohai Zhang ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Plant Protection ◽

Defense Responses ◽

Stilbene Synthase ◽

Myb Transcription Factor ◽

Wide Range ◽

Grapevine Leaves

Abstract Background Resveratrol is a naturally occurring plant stilbene that exhibits a wide range of valuable biological and pharmacological properties. Although the beneficial effects of trans-resveratrol to human health and plant protection against fungal pathogens and abiotic stresses are well-established, yet little is known about the molecular mechanisms regulating stilbene biosynthesis in plant defense progress. Results Here, we cloned and identified the Chinese wild grape (Vitis davidii) R2R3-MYB transcription factor VdMYB1, which activates defense responses against invading pathogen. VdMYB1 transcripts were significantly upregulated after inoculation with the grapevine powdery mildew fungus Erysiphe necator (Schw.) Burr. Transient expression analysis using onion epidermal cells and Arabidopsis thaliana protoplasts showed that VdMYB1 was localized in the nucleus. Yeast one-hybrid assays revealed that VdMYB1 acts as a transcriptional activator. Grapevine leaves transiently overexpressing VdMYB1 showed a lower number of fungal conidiophores compared with wild-type leaves. Overexpression of VdMYB1 in grapevine leaves did not alter the expression of genes in salicylic acid- and jasmonate-dependent pathways, but affected the expression of stilbene synthase (STS) genes, key regulators of flavonoid metabolism. Results of electrophoretic mobility shift assays and in vivo transcriptional activation assays showed that VdMYB1 binds to the MYB binding site (MYBBS) in the STS2 gene promoter, thus activating STS2 transcription. In heterologous expression assays using tobacco leaves, VdMYB1 activated STS2 gene expression and increased the accumulation of resveratrol. Conclusions Our study showed that VdMYB1 activates STS2 gene expression to positively regulate defense responses, and increases the content of resveratrol in leaves.

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MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206

The Journal of Cell Biology ◽

10.1083/jcb.200603039 ◽

2006 ◽

Vol 175 (1) ◽

pp. 77-85 ◽

Cited By ~ 225

Author(s):

Miriam I. Rosenberg ◽

Sara A. Georges ◽

Amy Asawachaicharn ◽

Erwin Analau ◽

Stephen J. Tapscott

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Transcriptional Activation ◽

Cell Types ◽

Muscle Differentiation ◽

Skeletal Muscle Differentiation ◽

Distinct Cell ◽

Muscle Genes ◽

Suppression Of Gene Expression ◽

Dystrophin Protein

Terminal differentiation of distinct cell types requires the transcriptional activation of differentiation-specific genes and the suppression of genes associated with the precursor cell. For example, the expression of utrophin (Utrn) is suppressed during skeletal muscle differentiation, and it is replaced at the sarcolemma by the related dystrophin protein. The MyoD transcription factor directly activates the expression of a large number of skeletal muscle genes, but also suppresses the expression of many genes. To characterize a mechanism of MyoD-mediated suppression of gene expression, we investigated two genes that are suppressed in fibroblasts converted to skeletal muscle by MyoD, follistatin-like 1 (Fstl1) and Utrn. MyoD directly activates the expression of a muscle-specific microRNA (miRNA), miR-206, which targets sequences in the Fstl1 and Utrn RNA, and these sequences are sufficient to suppress gene expression in the presence of miR-206. These findings demonstrate that MyoD, in addition to activating muscle-specific genes, induces miRNAs that repress gene expression during skeletal muscle differentiation.

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Coordinate gene expression of luteinizing hormone-releasing hormone (LHRH) and the LHRH-receptor after prolactin stimulation in the rat Nb2 T-cell line: implications for a role in immunomodulation and cell cycle gene expression

Molecular Endocrinology ◽

10.1210/me.9.1.44 ◽

1995 ◽

Vol 9 (1) ◽

pp. 44-53 ◽

Cited By ~ 21

Author(s):

T. M. Wilson

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

T Cell ◽

Luteinizing Hormone ◽

Cell Line ◽

Cell Cycle Gene ◽

Luteinizing Hormone Releasing Hormone ◽

Coordinate Gene Expression ◽

Cell Cycle Gene Expression ◽

Lhrh Receptor

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The neuronal calcium sensor family of Ca2+-binding proteins

Biochemical Journal ◽

10.1042/bj3530001 ◽

2000 ◽

Vol 353 (1) ◽

pp. 1-12 ◽

Cited By ~ 164

Author(s):

Robert D. BURGOYNE ◽

Jamie L. WEISS

Keyword(s):

Gene Expression ◽

Neurotransmitter Release ◽

Binding Proteins ◽

Current Knowledge ◽

Regulation Of Gene Expression ◽

Cell Types ◽

Nucleotide Metabolism ◽

Neuroendocrine Cells ◽

Calcium Sensor ◽

Neuronal Calcium Sensor

Ca2+ plays a central role in the function of neurons as the trigger for neurotransmitter release, and many aspects of neuronal activity, from rapid modulation to changes in gene expression, are controlled by Ca2+. These actions of Ca2+ must be mediated by Ca2+-binding proteins, including calmodulin, which is involved in Ca2+ regulation, not only in neurons, but in most other cell types. A large number of other EF-hand-containing Ca2+-binding proteins are known. One family of these, the neuronal calcium sensor (NCS) proteins, has a restricted expression in retinal photoreceptors or neurons and neuroendocrine cells, suggesting that they have specialized roles in these cell types. Two members of the family (recoverin and guanylate cyclase-activating protein) have established roles in the regulation of phototransduction. Despite close sequence similarities, the NCS proteins have distinct neuronal distributions, suggesting that they have different functions. Recent work has begun to demonstrate the physiological roles of members of this protein family. These include roles in the modulation of neurotransmitter release, control of cyclic nucleotide metabolism, biosynthesis of polyphosphoinositides, regulation of gene expression and in the direct regulation of ion channels. In the present review we describe the known sequences and structures of the NCS proteins, information on their interactions with target proteins and current knowledge about their cellular and physiological functions.

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Differential Regulation of Human Interferon A Gene Expression by Interferon Regulatory Factors 3 and 7

Molecular and Cellular Biology ◽

10.1128/mcb.01805-08 ◽

2009 ◽

Vol 29 (12) ◽

pp. 3435-3450 ◽

Cited By ~ 54

Author(s):

Pierre Génin ◽

Rongtuan Lin ◽

John Hiscott ◽

Ahmet Civas

Keyword(s):

Gene Expression ◽

Differential Expression ◽

Transcriptional Activation ◽

Cell Types ◽

Inhibitory Effect ◽

Human Interferon ◽

Gene Promoters ◽

Nucleotide Substitutions ◽

D Modules ◽

Different Cell Types

ABSTRACT Differential expression of the human interferon A (IFN-A) gene cluster is modulated following paramyxovirus infection by the relative amounts of active interferon regulatory factor 3 (IRF-3) and IRF-7. IRF-3 expression activates predominantly IFN-A1 and IFN-B, while IRF-7 expression induces multiple IFN-A genes. IFN-A1 gene expression is dependent on three promoter proximal IRF elements (B, C, and D modules, located at positions −98 to −45 relative to the mRNA start site). IRF-3 binds the C module of IFN-A1, while other IFN-A gene promoters are responsive to the binding of IRF-7 to the B and D modules. Maximal expression of IFN-A1 is observed with complete occupancy of the three modules in the presence of IRF-7. Nucleotide substitutions in the C modules of other IFN-A genes disrupt IRF-3-mediated transcription, whereas a G/A substitution in the D modules enhances IRF7-mediated expression. IRF-3 exerts dual effects on IFN-A gene expression, as follows: a synergistic effect with IRF-7 on IFN-A1 expression and an inhibitory effect on other IFN-A gene promoters. Chromatin immunoprecipitation experiments reveal that transient binding of both IRF-3 and IRF-7, accompanied by CBP/p300 recruitment to the endogenous IFN-A gene promoters, is associated with transcriptional activation, whereas a biphasic recruitment of IRF-3 and CBP/p300 represses IFN-A gene expression. This regulatory mechanism contributes to differential expression of IFN-A genes and may be critical for alpha interferon production in different cell types by RIG-I-dependent signals, leading to innate antiviral immune responses.

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