MAPK pathway mediates EGR-1-HSP70-dependent cigarette smoke-induced chemokine production

Li, Chao‐Jun; Ning, Wen; Matthay, Michael A.; Feghali‐Bostwick, Carol; Choi, Augustine M.K.

doi:10.1152/ajplung.00194.2006

Cited by 70 publications

(63 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[33][34][35][36][37][38] We have suggested that EGR-1 can also stimulate HSP70 elevation in an ERK 1/2-dependent manner, which is thought to regulate cigarette smoke-induced inflammatory processes. 18 Here we provide the first evidence that EGR-1 could activate MAPK ERK 1/2 in a positive feedback manner through increasing Ras prenylation by promoting GGPPS transcription in lung epithelial cells during CSE challenge (Figure 6). The sustainably activated ERK 1/2 in this positive feedback loop may lead to the progression of chronic lung inflammation and smoking-related pulmonary diseases.…”

Section: Discussionmentioning

confidence: 63%

“…[17][18][19] We found that EGR-1 activation normally precedes GGPPS expression when Beas-2B cells were stimulated with CSE. The accumulation of EGR-1 protein quickly increased within 30 minutes, and the protein level of GGPPS increased 1 to 6 hours after continuous CSE treatment (Figure 2A, upper panel).…”

Section: Egr-1 Can Promote Ggpps Transcription Under Cse Stimulationmentioning

confidence: 70%

“…17 In addition, EGR-1 can also stimulate HSP70 elevation in an ERK 1/2-dependent manner, which is thought to regulate the cigarette smoke-induced inflammatory processes. 18 In this manner, EGR-1 exerts an effect on chronic disease through the direct promotion of COPD-related gene expression under cigarette smoke exposure stress.…”

Section: Discussionmentioning

confidence: 99%

“…2 We have previously reported that human primary lung fibroblasts can synthesize matrix metalloproteinase (MMP) and chemokines in an EGR-1-dependent manner when exposed to cigarette smoke extract (CSE) stress. [17][18][19] To further understand the pathological functions of EGR-1 in pulmonary diseases during cigarette smoke-induced stress, we screened new target genes using chromatin immunoprecipitation (ChIP) methods. We have found that geranylgeranyl diphosphate synthase (GGPPS) is one of the novel EGR-1 target genes that mediate the function of EGR-1 during cigarette smoke exposure.…”

mentioning

confidence: 99%

See 3 more Smart Citations

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

Shen

Shao

Lai

et al. 2011

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Cigarette smoke activates the extracellular signal-regulated kinase (ERK) 1/2 mitogen activated-protein kinase pathway, which, in turn, is responsible for early growth response gene-1 (EGR-1) activation. Here we provide evidence that EGR-1 activation can also reactivate ERK 1/2 mitogen activated-protein kinase through a positive feedback loop through its target gene (geranylgeranyl diphosphate synthase) GGPPS. For the first time, the GGPPS gene is identified as a target of EGR-1, as EGR-1 can directly bind to the predicted consensus-binding site in the GGPPS promoter and regulate its transcription. Long-term observations show that there are two ERK 1/2 phosphorylation peaks after cigarette smoke extract stimulation in human lung epithelial Beas-2B cells. The first peak (at 10 minutes) is responsible for EGR-1 accumulation, and the second (at 4 hours) is diminished after the disruption of EGR-1 transcriptional activity. EGR-1 overexpression enhances Ras prenylation and membrane association in a GGPPS-dependent manner, and it augments ERK 1/2 activation. Likewise, a great reduction of the second peak of ERK 1/2 phosphorylation is observed during long-term cigarette smoke extract stimulation in cells where GGPPS is disrupted. Thus, we have uncovered an intricate positive feedback loop in which ERK 1/2-activated EGR-1 promotes ERK 1/2 reactivation through promoting GGPPS transcription, which might affect cigarette smoke-related lung pathological processes.

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Egr-1 Can Promote Ggpps Transcription Under Cse Stimulationmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

Shen

Shao

Lai

et al. 2011

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The expression of EGR-1 can be induced by a range of stimuli, which in many cases also serve as NF-kB activators (46)(47)(48). NF-kB and EGR-1 have been shown to cooperatively stimulate chemokine gene transcription (49).…”

Section: Discussionmentioning

confidence: 99%

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Park

Hun

Choi

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

In response to excessive nucleotide-binding oligomerization domain–containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-κB and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-κB regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-κB, which contributes to the suppression of Nod2-activated proinflammatory gene expression.

show abstract

Egr‐1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis)

Bhattacharyya

Fang

Tourtellotte

et al. 2012

The Journal of Pathology

136

114

View full text Add to dashboard Cite

Fibroblasts and myofibroblasts are the key effector cells executing physiologic tissue repair leading to regeneration on one hand, and pathological fibrogenesis leading to chronic fibrosing conditions on the other. Recent studies identify the multifunctional transcription factor Early Growth Response-1(Egr-1) as an important mediator of fibroblast activation triggered by diverse stimuli. Egr-1 has potent stimulatory effects on fibrotic gene expression, and aberrant Egr-1 expression or function is associated with animal models of fibrosis and human fibrotic disorders including emphysema, pulmonary fibrosis, pulmonary hypertension and systemic sclerosis. Pharmacological suppression or genetic targeting of Egr-1 blocks fibrotic responses in vitro and ameliorates experimental fibrosis in the skin and lung. In contrast, Egr-1 appear to acts as a negative regulator of hepatic fibrosis in mouse models, suggesting a context-dependent role in fibrosis. The Egr-1-binding protein Nab2 is an endogenous inhibitor of Egr-1-mediated signaling, and abrogates the stimulation of fibrotic responses induced by transforming growth factor-ß (TGF-ß). Moreover, mice deficient in Nab2 show excessive collagen accumulation in the skin. These observations highlight a previously unsuspected fundamental physiologic function for the Egr-1/Nab2 signaling axis in regulating fibrogenesis, and suggest that Egr-1 may be a potential novel therapeutic target in human diseases complicated by fibrosis. This review summarizes recent advances in understanding the regulation and complex functional role of Egr-1 and its related proteins and inhibitors in pathological fibrosis.

show abstract

MAPK pathway mediates EGR-1-HSP70-dependent cigarette smoke-induced chemokine production

Cited by 70 publications

References 36 publications

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Egr‐1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis)

Contact Info

Product

Resources

About