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Mucin Apoprotein Expression in COPD^*

^* From the Departments of Environmental Health, University of Cincinnati, Cincinnati, OH.

Correspondence to: George Leikauf, PhD, Director, Molecular Toxicology Division, Department of Environmental Health, University of Cincinnati, PO Box 670056, Cincinnati, OH 45267-0056; e-mail: leikaugd{at}uc.edu

Mucins, which are complex glycoproteins that provide the viscoelastic properties of mucus that are essential for the protection of the airways, are characterized by a variable-number tandem repeats (VNTR) region that may undergo alternate splicing during transcription. Such transcripts may yield multiple proteins via diverse post-translational modifications involving glycosylation (within each VNTR). Fifteen distinct mucin genes have been identified, with several mapping to chromosomal clusters (ie, 7q22 and 11p15.5), possibly having evolved by gene duplication. The deduced protein sequences can be subdivided into both membrane-associated mucins and secreted mucins. Membrane-associated mucins consist of cytoplasmic, transmembrane, and extracellular domains. The membrane-associated mucins MUC1, MUC4, and MUC11 have been localized to the lung. In addition to VNTRs, secreted mucins possess repeated cysteine-rich D-domains (which are important in polymerization). Secreted mucins that are localized to the lung include MUC2 (in cells with and without secretory granules), MUC5AC (in surface and submucosal mucous cells), MUC5B and MUC8 (in submucosal mucous cells), and MUC7 (in submucosal serous cells). Currently, little is known about the regulation of mucins in COPD patients. Recent studies with acrolein and cigarette smoke have suggested that MUC5AC is inducible (accompanied by epidermal growth factor [EGF] ligand formation and the activation of EGF receptor- dependent pathways), whereas MUC5B is constitutively expressed (increasing through gland enlargement). Similarly, little is known about the genetic determinants that control mucus hypersecretion, but preliminary findings in animal models suggest that intrastrain differences in acrolein-induced mucin formation are amenable to genetic analysis. As our understanding of the functional genomics of mucin biology increases, further clinical targets and therapeutic strategies are likely to emerge.

Key Words: airway • COPD • gene regulation • genetics • mucins • mucus hypersecretion • strain differences

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