The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

Chen, Shu Jen; Ning, Hongyan; Ishida, Wataru; Sodin‐Šemrl, Snežna; Takagawa, Shinsuke; Mori, Yasuji; Varga, John

doi:10.1074/jbc.m603270200

Cited by 152 publications

(166 citation statements)

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“…Egr-1 expression was rapidly and transiently induced by TGF-␤, and Egr-1 directly activated the transcription of COL1A2. 15 The present studies reveal that Egr-2 is also stimulated by TGF-␤ but via distinct regulatory pathways and with distinct kinetics characterized by slower, but more durable, induction compared with Egr-1. Endogenous Egr-2 was required for fibrotic responses, and overexpressed Egr-2 expression in normal fibroblasts was sufficient to stimulate collagen gene expression and myofibroblast differentiation in the absence of TGF-␤.…”

Section: Discussionmentioning

confidence: 53%

“…The expression of Egr-1 was rapidly induced by TGF-␤ in skin and lung fibroblasts, and Egr-1 was sufficient to stimulate the transcription of COL1A2 and other TGF-␤-inducible genes. 14,15 Moreover, mice with targeted deletion of Egr-1 were protected from bleomycin-induced fibrosis. 16 In contrast to Egr-1, the expression, regulation, and physiological roles of Egr-2 in connective tissue metabolism remain incompletely understood.…”

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confidence: 99%

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The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

Fang

Ooka

Bhattachyya

et al. 2011

The American Journal of Pathology

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Although the early growth response-2 (Egr-2, alias Krox20) protein shows structural and functional similarities to Egr-1, these two related early-immediate transcription factors are nonredundant. Egr-2 plays essential roles in peripheral nerve myelination, adipogenesis, and immune tolerance; however, its regulation and role in tissue repair and fibrosis remain poorly understood. We show herein that transforming growth factor (TGF)-␤ induced a Smad3-dependent sustained stimulation of Egr2 gene expression in normal fibroblasts. Overexpression of Egr-2 was sufficient to stimulate collagen gene expression and myofibroblast differentiation, whereas these profibrotic TGF-␤ responses were attenuated in Egr-2-depleted fibroblasts. Genomewide transcriptional profiling revealed that multiple genes associated with tissue remodeling and wound healing were up-regulated by Egr-2, but the Egr-2-regulated gene expression profile overlapped only partially with the Egr-1-regulated gene profile. Levels of Egr-2 were elevated in lesional tissue from mice with bleomycin-induced scleroderma. Moreover, elevated Egr-2 was noted in biopsy specimens of skin and lung from patients with systemic sclerosis.These results provide the first evidence that Egr-2 is a functionally distinct transcription factor that is both necessary and sufficient for TGF-␤-induced profibrotic responses and is aberrantly expressed in lesional tissue in systemic sclerosis and in a murine model of scleroderma. Together, these findings suggest that Egr-2 plays an important nonredundant role in the pathogenesis of fibrosis. Targeting Egr-2 might represent a novel therapeutic strategy to control fibrosis.

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

Fang

Ooka

Bhattachyya

et al. 2011

The American Journal of Pathology

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“…Early growth response (Egr)-1 is a zinc-finger transcription factor that is up-regulated in response to TGF-␤ and regulates collagen gene expression. 13 Egr-1 orchestrates the cellular response to several growth factors and other exogenous stimuli 14 -15 and is likely to act downstream of multiple pro-fibrotic agents to regulate transcription of fibrosis-associated genes.…”

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confidence: 99%

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Yasuoka

Hsu

Ruiz

et al. 2009

The American Journal of Pathology

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We have previously shown that insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that

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“…In this study, we examined the relationship between apoptosis, the rate of seminal TGFß1, the rate of the different forms of glutathione (GSHt, GSSG, GSHr) and fragmentation of the sperm DNA. As far as we know, this is the first analysis that examines all these parameters simultaneously [41][42][43][44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

“…The presence of apoptosis-related DNA strand breaks in spermatozoa was evaluated by the terminal desoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nickend labeling (TUNEL) assay, using the ApopTag® Apoptosis Detection Kits (QBiogene, Paris, France) in controls and patients [40][41][42][43][44].…”

Section: Measurement Of Dna Fragmentationmentioning

confidence: 99%

Effect of Seminal Transforming Growth Factorß1 (TGFß1) and Glutathione on Apoptosis in Spermatozoa from Tunisian Infertile Men

Ben Ali

2017

Andrology

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We aimed to compare the effect of TGFB1 and glutathione on sperm necrosis in three groups of patients with increased necrospermia. The study included 120 men aged 37.6 ± 4.6 years consulting for sterility of the couple. Patients were subdivided into three groups according to the percentage of necrotic spermatozoa: necrospermia<30%; N=40), moderate necrozoospermia (50-80%, n=45) and severe necrozoospermia (>80%) For each patient, the sperm parameters were evaluated according to WHO standards, TGFB1 and glutathione Oxidized and reduced was carried out by the ELISA technique and by spectrophotometry respectively. We found a significant increase in the levels of TGFβ1 and DFI in moderate and severe necrospermia groups and positive correlations between these two factors and sperm parameters (numeration, mobility and morphology). In addition, a significant decrease in seminal GHSt was observed in the necrozoospermic groups compared to the control group. A strong correlation was observed between the degree of necrozoospermia and the fragmentation of sperm DNA (r=0.878, p=0.001). In addition, a significant positive correlation between TGFβ1 and DFI in the two groups of patients with moderate necrospermia (r=0.43, p<0.05) and severe necrospermia (r=0.52, p<0.05). This confirms that seminal TGFβ1 is a factor in the fragmentation of spermatozoa DNA. These results suggest that decreased glutathione and increased seminal TGFβ1 are important risk factors that can lead to a succession of morphological and functional alterations of spermatozoa resulting in necrozoospermia. Their perturbation in seminal plasma can lead to mediocre results of medically assisted procreation.

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The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

Abstract: Transforming growth factor-␤ (TGF-␤

Cited by 152 publications

References 84 publications

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Effect of Seminal Transforming Growth Factorß1 (TGFß1) and Glutathione on Apoptosis in Spermatozoa from Tunisian Infertile Men

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