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-Induced MUC5AC Overexpression1
* Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; and
The Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030
Mucus secretion is an important protective mechanism for the luminal lining of open tubular organs, but mucin overproduction in the respiratory tract can exacerbate the inflammatory process and cause airway obstruction. Production of MUC5AC, a predominant gel-forming mucin secreted by airway epithelia, can be induced by various inflammatory mediators such as prostaglandins. The two major prostaglandins involved in inflammation are PGE2 and PGF2
. PGE2-induced mucin production has been well studied, but the effect of PGF2 on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF2 on MUC5AC production, we investigated the signal transduction of PGF2 associated with this effect using normal human tracheobronchial epithelial cells. Our results demonstrated that PGF2 induces MUC5AC overproduction via a signaling cascade involving protein kinase C, ERK, p90 ribosomal S6 protein kinase, and CREB. The regulation of PGF2-induced MUC5AC expression by CREB was further confirmed by cAMP response element-dependent MUC5AC promoter activity and by interaction between CREB and MUC5AC promoter. The abrogation of all downstream signaling activities via suppression of each signaling molecule along the pathway indicates that a single pathway from PGF2 receptor to CREB is responsible for inducing MUC5AC overproduction. As CREB also mediates mucin overproduction induced by PGE2 and other inflammatory mediators, our findings have important clinical implications for the management of airway mucus hypersecretion.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Heart, Lung, and Blood Institute Grant R01-HL-077556 (to J.S.K.) and National Cancer Institute Cancer Center Support Grant CA-16672 (to The University of Texas M. D. Anderson Cancer Center). This work was also supported in part by the intramural research program of the National Institutes of Health, National Institutes of Environmental Health Sciences (to D.C.Z.).
2 W.-C.C. and S.-H.R. contriubed equally to this paper.
3 Address correspondence and reprint requests to Dr. Ja Seok Koo, Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail address: jskoo{at}mdanderson.org
4 Abbreviations used in this paper: NHTBE, normal human tracheobronchial epithelial; β-gal, β-galactosidase; ChIP, chromatin immunoprecipitation; COX2, cyclooxygenase 2; CRE, cyclic AMP response element; PKA, protein kinase A; PKC, protein kinase C; RSK, p90 ribosomal S6 protein kinase; siRNA, small interfering RNA.
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