Elastase-released Epidermal Growth Factor Recruits Epidermal Growth Factor Receptor and Extracellular Signal-regulated Kinases to Down-regulate Tropoelastin mRNA in Lung Fibroblasts

DiCamillo, Sandra J.; Carreras, Isabel; Stone, Phillip J.; Nugent, Matthew A.; Foster, Jeffrey S.; Panchenko, Mikhail P.

doi:10.1074/jbc.m200243200

Cited by 59 publications

(57 citation statements)

References 76 publications

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“…Several observations were made. 1) We found that, similar to primary neonatal rat lung fibroblasts (5), NE signals to tropoelastin mRNA downregulation in RFL-6 cells via release of EGF-like ligands (found in both type of cells) and TGF-␣-like polypeptides (found only in RFL-6 cells) and subsequently activates the EGFR/MEK/ERK cascade, suggesting that this might be a common response of the various elastogenic cells to elastolytic injury. 2) We demonstrated that the EGFR/MEK/ERK-dependent tropoelastin mRNA downregulation actually translates into major reduction of tropoelastin protein expression and insoluble elastin levels, signifying the overall inhibitory impact of EGFR/MEK/ERK cascade signaling on elastogenesis in lung fibroblasts.…”

Section: Discussionmentioning

confidence: 58%

“…Previously, investigators in our group have demonstrated that NE releases biologically active EGFR ligands, such as EGF-like polypeptides, and initiates EGFR-dependent MEK/ ERK activation resulting in downregulation of tropoelastin mRNA levels in neonatal rat lung fibroblasts (5). In the present study we aimed to dissect the mechanism of EGFR/MEK/ ERK-mediated tropoelastin mRNA downregulation, as well as to determine its impact on elastogenesis in lung fibroblasts.…”

Section: Resultsmentioning

confidence: 94%

“…The elastase/anti-elastase imbalance in the lung is associated with the release/induction of growth factors and cytokines (2,29), which are known to positively [transforming growth factor-␤ (TGF-␤) (22,41)] and negatively [interleukin-1␤ (IL-1␤) (1), tumor necrosis factor-␣ (TNF-␣) (12), or basic fibroblast growth factor (bFGF) (31)] modulate elastin gene expression in lung fibroblasts. Previous studies in our laboratory demonstrated that exposure of neonatal rat lung fibroblasts to neutrophil elastase (NE) and/or pancreatic elastase results in the release of biologically active epidermal growth factor receptor (EGFR) ligand(s), such as polypeptides immunochemically related to epidermal growth factor (EGF) (5) and heparinbinding EGF-like growth factor (18), leading to EGFR activation and initiation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinases 1 and 2 (ERK) signaling to tropoelastin mRNA downregulation (5). Interestingly, in airway epithelial cells, NE was shown to release TGF-␣-like polypeptides followed by EGFR transactivation and signaling to increase expression of a major respiratory mucin, Muc5ac (14).…”

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confidence: 99%

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Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts

DiCamillo

Yang²,

Toselli³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Discussionmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 94%

mentioning

confidence: 99%

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Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts

DiCamillo

Yang²,

Toselli³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In addition to its described role in tumour cell invasion and metastasis, the serine protease PMN-E may, similar as has been suggested for uPA for human ovarian carcinoma cells (Fischer et al, 1998) and breast cancer cells (Foekens et al, 1995), provoke cell proliferation via enzymatic activation of several growth factor (receptor) pathways. In this respect, the ability of elastase to cleave or activate several growth factors or receptors, such as EGF and EGF receptor (Di Camillo et al, 2002), IL-2 and IL-6 receptor (Bank et al, 1999), stromal cellderived factor-1 (Valenzuela-Fernandez et al, 2002), supports such a local elastase-directed growth interfering mechanism.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease

et al. 2003

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Besides a variety of other proteases, polymorphonuclear leukocyte elastase (PMN-E) is also suggested to play a role in the processes of tumour cell invasion and metastasis. Yet, there is only limited data available on the relation between the tumour level of PMN-E and prognosis in patients with primary breast cancer, and no published information exists on its relation with the efficacy of response to systemic therapy in patients with advanced breast cancer. In the present study, we have measured with enzyme-linked immunosorbent assay the levels of total PMN-E in cytosolic extracts of 463 primary breast tumours, and have correlated their levels with the rate and duration of response on first-line tamoxifen therapy (387 patients) or chemotherapy (76 patients) in patients with locally advanced and/or distant metastatic breast cancer. Furthermore, the probabilities of progression-free survival and postrelapse survival were studied in relation to the tumour levels of PMN-E. Our results show that in logistic regression analysis for response to tamoxifen treatment in patients with advanced disease, high PMN-E tumour levels were associated with a poor rate of response compared with those with low PMN-E levels (odds ratio: OR, 0.40; 95% CI, 0.22 -0.73; P ¼ 0.003). After correction for the contribution of the traditional predictive factors in multivariate analysis, the tumour PMN-E status was an independent predictor of response (P ¼ 0.01). Furthermore, a high tumour PMN-E level was related with a poor progression-free survival (Po0.001) and postrelapse survival (P ¼ 0.002) in a time-dependent analysis. In contrast, the tumour level of PMN-E was not significantly related with the efficacy of response to first-line chemotherapy in patients with advanced breast cancer. Our present results suggest that PMN-E is an independent predictive marker for the efficacy of tamoxifen treatment in patients with advanced breast cancer.

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“…QRT-PCR also verified TGF-␤1 and PDGFRA expression, which were detected by SAGE alone (Table 2). Of these eight genes, EGR-1 (24), FOS (25), and TGF-␤1 (26) are well known COPD-responsive genes. To our knowledge, the other genes are not known to be associated with COPD or smoking.…”

Section: Confirmation Of Candidate Genes By Qrt-pcrmentioning

confidence: 99%

Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease

Ning

Kaminski

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

301

269

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To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from COPD and control smokers. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.5-fold up-or down-regulated). Microarray analysis using the same RNA source detected 261 transcripts that were differentially expressed to a significant degree between GOLD-2 and GOLD-0 smokers. We confirmed the altered expression of a select number of genes by using real-time quantitative RT-PCR. These genes encode for transcription factors (EGR1 and FOS), growth factors or related proteins (CTGF, CYR61, CX3CL1, TGFB1, and PDGFRA), and extracellular matrix protein (COL1A1). Immunofluorescence studies on the same lung specimens localized the expression of Egr-1, CTGF, and Cyr61 to alveolar epithelial cells, airway epithelial cells, and stromal and inflammatory cells of GOLD-2 smokers. Cigarette smoke extract induced Egr-1 protein expression and increased Egr-1 DNA-binding activity in human lung fibroblast cells. Cytomix (tumor necrosis factor ␣, IL-1␤, and IFN-␥) treatment showed that the activity of matrix metalloproteinase-2 (MMP-2) was increased in lung fibroblasts from EGR1 control (؉/؉) mice but not detected in that of EGR1 null (؊/؊) mice, whereas MMP-9 was regulated by EGR1 in a reverse manner. Our study represents the first comprehensive analysis of gene expression on GOLD-2 versus GOLD-0 smokers and reveals previously unreported candidate genes that may serve as potential molecular targets in COPD.

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Elastase-released Epidermal Growth Factor Recruits Epidermal Growth Factor Receptor and Extracellular Signal-regulated Kinases to Down-regulate Tropoelastin mRNA in Lung Fibroblasts

Abstract: Elastase/anti-elastase imbalance is a hallmark of emphysema, a chronic obstructive pulmonary disease associated with the rupture and inefficient repair of interstitial elastin. We report that neutrophil elastase (

Cited by 59 publications

References 76 publications

Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts

Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts

Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease

Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease

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