Control of Mucin Transcription by Diverse Injury-induced Signaling Pathways

Basbaum, Carol; Lemjabbar, Hassan; Longphre, Malinda; Li, Daizong; Gensch, Erin; McNamara, Nancy

doi:10.1164/ajrccm.160.supplement_1.12

Cited by 121 publications

(107 citation statements)

References 23 publications

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“…1D), indicating that smoke induces MUC5AC at the level of transcription. Despite the involvement of EGFR in the induction of MUC5AC by smoke (8,9), saturating concentrations of EGF (25-500 ng/ml) evoked a relatively small (2.5-fold) response (Fig. 1D) in agreement with Perrais et al (14).…”

Section: Muc5ac Mucin Is Up-regulated By Smoke In Vivo and Insupporting

confidence: 88%

“…A breakthrough in understanding this phenomenon came with the realization that smoke directly stimulates mucin synthesis in epithelial cells (8,9). The signaling cascade mediating this phenomenon has been shown to involve EGFR at the cell surface, but the distal elements of the pathway have not been described.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, however, smoke itself can induce mucin synthesis in lung cells (8,9). The question of how this occurs is complex in that smoke, a composite of irritant molecules including acetaldehyde, hydroquinone, formaldehyde, benzo-[a]pyrene, cresol, nicotine, catechol, acrolein, coumarin, anthracene, nitrogen oxides, and heavy metals (10, 11) may act on lung epithelial cells in diverse ways.…”

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confidence: 99%

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Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Gensch

Gallup

Sucher

et al. 2004

Journal of Biological Chemistry

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141

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In smokers' lungs, excessive mucus clogs small airways, impairing respiration and promoting recurrent infection. A breakthrough in understanding this pathology was the realization that smoke could directly stimulate mucin synthesis in lung epithelial cells and that this phenomenon was dependent on the cell surface receptor for epidermal growth factor, EGFR. Distal steps in the smoke-triggered pathway have not yet been determined. We report here that the predominant airway mucin (MUC5AC) undergoes transcriptional up-regulation in response to tobacco smoke; this is mediated by an AP-1-containing response element, which binds JunD and Fra-2. These transcription factors require phosphorylation by upstream kinases JNK and ERK, respectively. Whereas ERK activation results from the upstream activation of EGFR, JNK activation is chiefly EGFR-independent. Our experiments demonstrated that smoke activates JNK via a Src-dependent, EGFRindependent signaling cascade initiated by smoke-induced reactive oxygen species. Taken together with our earlier results, these data indicate that the induction of mucin by smoke is the combined effect of mutually independent, reactive oxygen species activation of both EGFR and JNK.The primary cause of morbidity in chronic bronchitis is mucin overproduction, a phenomenon for which the molecular pathogenesis is unknown. Inflammatory cells are abundant in smokers' airways (1-3) and are capable of stimulating mucin production (4 -7), suggesting that at least some of the excessive mucin in smokers' lungs is secondary to inflammation.In addition, however, smoke itself can induce mucin synthesis in lung cells (8,9). The question of how this occurs is complex in that smoke, a composite of irritant molecules including acetaldehyde, hydroquinone, formaldehyde, benzo-[a]pyrene, cresol, nicotine, catechol, acrolein, coumarin, anthracene, nitrogen oxides, and heavy metals (10, 11) may act on lung epithelial cells in diverse ways. For example, the induction of cytochrome P450 by tobacco smoke (12) is mediated by binding of the aryl hydrocarbon nuclear receptor to a dioxin response element in the 5Ј-flank of the gene, but the induction of the ␥-glutamylcysteine synthetase heavy subunit (␥-GCS-HS) gene is mediated by the binding of a c-Jun/c-Jun homodimer to an AP-1-like response element (13).Previous reports have implicated the receptor for epidermal growth factor (EGFR) 1 in the induction of mucin gene MUC5AC by smoke (9). Consistent with a role for EGFR in mucin induction, an EGF response element has been identified 200 bp upstream of the MUC5AC gene (14). The response of this element to EGFR ligands EGF and transforming growth factor-␣ is mediated by Sp1. One might predict from these data that the induction of MUC5AC by smoke would depend on interaction between the EGF response element at Ϫ200 bp and Sp1.In contrast, in the present study we show that MUC5AC is controlled principally by a smoke response element ϳ3 kb upstream of the EGF response element. This element is AP-1-dependent and is bound by Ju...

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Section: Muc5ac Mucin Is Up-regulated By Smoke In Vivo and Insupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Gensch

Gallup

Sucher

et al. 2004

Journal of Biological Chemistry

Self Cite

141

120

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“…PMA can substitute for diacylglycerol, the endogenous activator of PKC, and it has been used as a model agent to study the mechanisms utilized by growth factors, hormones, and cytokines to regulate growth and differentiation of cells (9 -11). Phorbol esters, as well as cytokines and bacterial lipopolysaccharides, have been shown to up-regulate mucin genes (12)(13)(14)(15)(16)(17). We recently reported that PMA up-regulates several mucin genes, including MUC2, in colon cancer cell lines (18).…”

mentioning

confidence: 99%

Phorbol 12-Myristate 13-Acetate Up-regulates the Transcription of MUC2Intestinal Mucin via Ras, ERK, and NF-κB

Lee

Ahn

Crawley

et al. 2002

Journal of Biological Chemistry

102

106

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“…Upregulation of mucin genes during disease and inflammation may be critical for the overproduction and hypersecretion of mucus that contributes to airway obstruction. Several studies demonstrate that inflammatory mediators (e.g., IL-1, TNF-α), neutrophil-derived proteases, and bacterial products can elicit the overexpression of mucin genes (e.g., Muc5AC) in airway epithelial cells (42)(43)(44).…”

Section: Mucous Cell Metaplasia In Respiratory Diseasementioning

confidence: 99%

Effects of ozone and endotoxin coexposure on rat airway epithelium: potentiation of toxicant-induced alterations.

Wagner

Hotchkiss

Harkema

2001

Environ Health Perspect

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Tropospheric ozone is the major oxidizing component in photochemical smog and is one of the most pervasive problems to human health of the criteria air pollutants for which the National Ambient Air Quality Standards have been designated by the Clean Air Act. Although many adverse health effects of ozone exposure have been documented in both humans and laboratory animals, controversy surrounds the establishment and implementation of ozone standards set forth by the U.S. Environmental Protection Agency. Because people are commonly exposed to more than one air pollutant at a time, studies that examine coexposures to airborne materials may be more relevant for assessing their risks to human health. Airborne biogenic substances such as pollens, spores, and bacterial products are ubiquitous in the environment, and when inhaled can cause adverse respiratory symptoms. One such biogenic agent, bacterial endotoxin, is a potent stimulus of airway inflammation and is a ubiquitous airborne contaminant commonly found in domestic, agricultural, and industrial settings. Little is known about the interaction of exposures to biogenic substances and criteria air pollutants such as ozone. In the last few years we have performed a series of studies in rodents that examined the biologic responses of the respiratory epithelium after airway exposures to both endotoxin and ozone. When exposed to ozone (0.5 ppm 8 hr/day for 3 days), Fischer rats develop lesions in the nasal transitional epithelium, whereas intranasal instillation of endotoxin (20 microg) elicits epithelial lesions in the respiratory epithelium of the nose and conducting airways. Our studies were designed to examine how exposure to one toxicant may affect the airway epithelial lesions induced by the other toxicant. We investigated the potential role of acute inflammation in the enhancement of airway epithelial lesions after exposure of these two toxicants in neutrophil-sufficient and neutrophil-deficient rodents. A summary of these results indicates that epithelial and inflammatory responses to coexposure of these two pollutants are greater than those elicited by either agent alone. Interestingly, each toxicant enhances the epithelial alterations induced by the other. Furthermore, the synergistic effects elicited by coexposure to ozone and endotoxin are mediated partly by neutrophils. These studies provided some new insights into how inhaled co-pollutants interact to initiate and promote alterations of airway epithelium. Further studies with these and other air pollutants will help define their true risk to human health.

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Control of Mucin Transcription by Diverse Injury-induced Signaling Pathways

Cited by 121 publications

References 23 publications

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Phorbol 12-Myristate 13-Acetate Up-regulates the Transcription of MUC2Intestinal Mucin via Ras, ERK, and NF-κB

Effects of ozone and endotoxin coexposure on rat airway epithelium: potentiation of toxicant-induced alterations.

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