scholarly journals Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target

2012 ◽  
Vol 444 (2) ◽  
pp. 343-355 ◽  
Author(s):  
Alejandro Giraldo ◽  
Oliver P. T. Barrett ◽  
Marcus J. Tindall ◽  
Stephen J. Fuller ◽  
Emre Amirak ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Growth Response ◽  
Target Genes ◽  
Feedback Regulation ◽  
Immediate Early Genes ◽  
Immediate Early ◽  
Cardiomyocyte Hypertrophy ◽  
Negative Feedback Regulation ◽  
Endothelin 1 ◽  
Early Genes

Endothelin-1 promotes cardiomyocyte hypertrophy by inducing changes in gene expression. Immediate early genes including Atf3 (activating transcription factor 3), Egr1 (early growth response 1) and Ptgs2 (prostaglandin-endoperoxide synthase 2) are rapi-dly and transiently up-regulated by endothelin-1 in cardiomyocytes. Atf3 regulates the expression of downstream genes and is implicated in negative feedback regulation of other immediate early genes. To identify Atf3-regulated genes, we knocked down Atf3 expression in cardiomyocytes exposed to endothelin-1 and used microarrays to interrogate the transcriptomic effects. The expression of 23 mRNAs (including Egr1 and Ptgs2) was enhanced and the expression of 25 mRNAs was inhibited by Atf3 knockdown. Using quantitative PCR, we determined that knockdown of Atf3 had little effect on up-regulation of Egr1 mRNA over 30 min, but abolished the subsequent decline, causing sustained Egr1 mRNA expression and enhanced protein expression. This resulted from direct binding of Atf3 to the Egr1 promoter. Mathematical modelling established that Atf3 can suffice to suppress Egr1 expression. Given the widespread co-regulation of Atf3 with Egr1, we suggest that the Atf3–Egr1 negative feedback loop is of general significance. Loss of Atf3 caused abnormal cardiomyocyte growth, presumably resulting from the dysregulation of target genes. The results of the present study therefore identify Atf3 as a nexus in cardiomyocyte hypertrophy required to facilitate the full and proper growth response.

scholarly journals Engineering combinatorial and dynamic decoders using synthetic immediate-early genes

2019 ◽  
Author(s):  
Pavithran T. Ravindran ◽  
Maxwell Z. Wilson ◽  
Siddhartha G. Jena ◽  
Jared E. Toettcher
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Immediate Early Genes ◽  
Immediate Early Gene ◽  
Early Gene ◽  
Immediate Early ◽  
Specific Target ◽  
Early Genes

AbstractFor tissues to grow and function properly, cells must coordinate actions such as proliferation, differentiation and apoptosis. This coordination is achieved in part by the activation of intracellular signaling pathways that trigger the expression of context-specific target genes. While the function of these natural circuits has been actively studied, synthetic biology provides additional powerful tools for deconstructing, repurposing, and designing novel signal-decoding circuits. Here we report the construction of synthetic immediate-early genes (synIEGs), target genes of the Erk signaling pathway that implement complex, user-defined regulation and can be monitored through the use of live-cell biosensors to track transcription and translation. We demonstrate the power and flexibility of this approach by confirming Erk duration-sensing by the FOS immediate-early gene, elucidating how the BTG2 gene is regulated by transcriptional activation and translational repression after growth-factor stimulation, and by designing a synthetic immediate-early gene that responds with AND-gate logic to the combined presence of growth factor and DNA damage stimuli. Our work paves the way to defining the molecular circuits that link signaling pathways to specific target genes, highlighting an important role for post-transcriptional regulation in signal decoding that may be masked by analyses of RNA abundance alone.

Intestinal perfusion induces rapid activation of immediate-early genes in weaning rats

2001 ◽  
Vol 281 (4) ◽  
pp. R1274-R1282 ◽  
Author(s):  
Lan Jiang ◽  
Heather Lawsky ◽  
Relicardo M. Coloso ◽  
Mary A. Dudley ◽  
Ronaldo P. Ferraris
Keyword(s):  
Mrna Expression ◽  
Target Genes ◽  
De Novo ◽  
Immediate Early Genes ◽  
Regulatory Elements ◽  
Intestinal Perfusion ◽  
Immediate Early ◽  
Mrna Levels ◽  
Early Genes

C- fos and c- jun are immediate-early genes (IEGs) that are rapidly expressed after a variety of stimuli. Products of these genes subsequently bind to DNA regulatory elements of target genes to modulate their transcription. In rat small intestine, IEG mRNA expression increases dramatically after refeeding following a 48-h fast. We used an in vivo intestinal perfusion model to test the hypothesis that metabolism of absorbed nutrients stimulates the expression of IEGs. Compared with those of unperfused intestines, IEG mRNA levels increased up to 11 times after intestinal perfusion for 0.3–4 h with Ringer solutions containing high (100 mM) fructose (HF), glucose (HG), or mannitol (HM). Abundance of mRNA returned to preperfusion levels after 8 h. Levels of c- fos and c- jun mRNA and proteins were modest and evenly distributed among enterocytes lining the villi of unperfused intestines. HF and HM perfusion markedly enhanced IEG mRNA expression along the entire villus axis. The perfusion-induced increase in IEG expression was inhibited by actinomycin-D. Luminal perfusion induces transient but dramatic increases in c- fos and c- jun expression in villus enterocytes. Induction does not require metabolizable or absorbable nutrients but may involve de novo gene transcription in cells along the villus.

scholarly journals Engineering combinatorial and dynamic decoders using synthetic immediate-early genes

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Pavithran T. Ravindran ◽  
Maxwell Z. Wilson ◽  
Siddhartha G. Jena ◽  
Jared E. Toettcher
Keyword(s):  
Intracellular Signaling ◽  
Target Genes ◽  
Immediate Early Genes ◽  
Tissue Level ◽  
Early Gene ◽  
Immediate Early ◽  
Early Genes ◽  
Natural Target ◽  
Context Specific ◽  
External Stimuli

AbstractMany cell- and tissue-level functions are coordinated by intracellular signaling pathways that trigger the expression of context-specific target genes. Yet the input–output relationships that link pathways to the genes they activate are incompletely understood. Mapping the pathway-decoding logic of natural target genes could also provide a basis for engineering novel signal-decoding circuits. Here we report the construction of synthetic immediate-early genes (SynIEGs), target genes of Erk signaling that implement complex, user-defined regulation and can be monitored by using live-cell biosensors to track their transcription and translation. We demonstrate the power of this approach by confirming Erk duration-sensing by FOS, elucidating how the BTG2 gene is differentially regulated by external stimuli, and designing a synthetic immediate-early gene that selectively responds to the combination of growth factor and DNA damage stimuli. SynIEGs pave the way toward engineering molecular circuits that decode signaling dynamics and combinations across a broad range of cellular contexts.

Induction of immediate-early genes by angiotensin II and endothelin-1 in adult rat cardiomyocytes

1993 ◽  
Vol 11 (9) ◽  
pp. 927-934 ◽  
Author(s):  
Ludwig Neyses ◽  
Janis Nouskas ◽  
Joachim Luyken ◽  
Stefan Fronhoffs ◽  
Silke Oberdorf ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Immediate Early Genes ◽  
Immediate Early ◽  
Rat Cardiomyocytes ◽  
Endothelin 1 ◽  
Adult Rat ◽  
Early Genes

scholarly journals The immediate-early growth response in regenerating liver and insulin-stimulated H-35 cells: comparison with serum-stimulated 3T3 cells and identification of 41 novel immediate-early genes.

1991 ◽  
Vol 11 (1) ◽  
pp. 381-390 ◽  
Author(s):  
K L Mohn ◽  
T M Laz ◽  
J C Hsu ◽  
A E Melby ◽  
R Bravo ◽  
...  
Keyword(s):  
Growth Response ◽  
Immediate Early Genes ◽  
Cell Types ◽  
Early Growth ◽  
Immediate Early ◽  
Regenerating Liver ◽  
3T3 Cells ◽  
Early Growth Response ◽  
Early Genes ◽  
Different Cell Types

Liver regeneration provides a unique system for analysis of mitogenesis in intact, fully developed animals. Cellular immediate-early genes likely play an important role in cell cycle regulation and have been extensively studied in mitogen-stimulated fibroblasts lymphocytes but not in liver. We have begun to characterize the immediate-early growth response genes of mitogen-stimulated liver cells, specifically, regenerating liver and insulin-stimulated Reuber H-35 hepatoma cells, and to address differences in growth response between different cell types. Through subtraction and differential screening of cDNA libraries from regenerating liver and insulin-treated H-35 cells, we have extensively characterized 341 differentially expressed clones and identified 52 immediate-early genes. These genes have been partially sequenced and subjected to Northern (RNA) blot analysis, and 41 appear to be novel. Surprisingly, two-thirds of these genes are also expressed in BALB/c 3T3 cells, but only 10 were identified in previous studies of 3T3 cells, and of these, 6 include well-known genes like jun and fos, and only 4 are novel. Approximately one-third of the immediate-early genes identified in mitogen-stimulated liver cells or serum-stimulated NIH 3T3 cells are expressed in a tissue-specific fashion, indicating that cell type-specific regulation of the proliferative response occurs during the immediate-early period. Our findings indicate that the immediate-early response is unusually complex for the first step in a regulatory cascade, suggesting that multiple pathways must be activated. The abundance of immediate-early genes and the highly varied pattern of their expression in different cell types suggest that the tissue specificity of the proliferative response arises from the particular set of these genes expressed in a given tissue.

Genome-wide identification of palmitate-regulated immediate early genes and target genes in pancreatic beta-cells reveals a central role of NF-κB

2012 ◽  
Vol 39 (6) ◽  
pp. 6781-6789 ◽  
Author(s):  
Hyung Jin Choi ◽  
Seungwoo Hwang ◽  
Se-Hee Lee ◽  
You Ri Lee ◽  
Jiyon Shin ◽  
...  
Keyword(s):  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Target Genes ◽  
Immediate Early Genes ◽  
Immediate Early ◽  
Early Genes ◽  
Genome Wide

The immediate-early growth response in regenerating liver and insulin-stimulated H-35 cells: comparison with serum-stimulated 3T3 cells and identification of 41 novel immediate-early genes

1991 ◽  
Vol 11 (1) ◽  
pp. 381-390
Author(s):  
K L Mohn ◽  
T M Laz ◽  
J C Hsu ◽  
A E Melby ◽  
R Bravo ◽  
...  
Keyword(s):  
Growth Response ◽  
Immediate Early Genes ◽  
Cell Types ◽  
Early Growth ◽  
Immediate Early ◽  
Regenerating Liver ◽  
3T3 Cells ◽  
Early Growth Response ◽  
Early Genes ◽  
Different Cell Types

Liver regeneration provides a unique system for analysis of mitogenesis in intact, fully developed animals. Cellular immediate-early genes likely play an important role in cell cycle regulation and have been extensively studied in mitogen-stimulated fibroblasts lymphocytes but not in liver. We have begun to characterize the immediate-early growth response genes of mitogen-stimulated liver cells, specifically, regenerating liver and insulin-stimulated Reuber H-35 hepatoma cells, and to address differences in growth response between different cell types. Through subtraction and differential screening of cDNA libraries from regenerating liver and insulin-treated H-35 cells, we have extensively characterized 341 differentially expressed clones and identified 52 immediate-early genes. These genes have been partially sequenced and subjected to Northern (RNA) blot analysis, and 41 appear to be novel. Surprisingly, two-thirds of these genes are also expressed in BALB/c 3T3 cells, but only 10 were identified in previous studies of 3T3 cells, and of these, 6 include well-known genes like jun and fos, and only 4 are novel. Approximately one-third of the immediate-early genes identified in mitogen-stimulated liver cells or serum-stimulated NIH 3T3 cells are expressed in a tissue-specific fashion, indicating that cell type-specific regulation of the proliferative response occurs during the immediate-early period. Our findings indicate that the immediate-early response is unusually complex for the first step in a regulatory cascade, suggesting that multiple pathways must be activated. The abundance of immediate-early genes and the highly varied pattern of their expression in different cell types suggest that the tissue specificity of the proliferative response arises from the particular set of these genes expressed in a given tissue.

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