Genome-Wide Search and Identification of a Novel Gel-Forming Mucin MUC19/Muc19 in Glandular Tissues

Abstract

Gel-forming mucins are major contributors to the viscoelastic properties of mucus secretion. Currently, four gel-forming mucin genes have been identified: MUC2, MUC5AC, MUC5B, and MUC6. All these genes have five major cysteine-rich domains (four von Willebrand factor [vWF] C or D domains and one Cystine-knot [CT] domain) as their distinctive features, in contrast to other non-gel-forming type of mucins. The CT domain is believed to be involved in the initial mucin dimer formation and have very succinct relationship between different gel-forming mucins across different species. Because of gene duplication and evolutional modification, it is very likely that other gel-forming mucin genes exist. To search for new gel-forming mucin candidate genes, a "Hidden Markov Model"(HMM) was built from the common features of the CT domains of those gel-forming mucins. By using this model to screen all protein databases as well as the six-frame translated expression sequence tag and translated human genomic databases, we identified a locus located at the peri-centromere region of human chromosome 12 and the corresponding homologous region of mouse chromosome 15. We cloned the 3' end of this gene and its mouse homolog. We found one vWF C domain, one CT domain, and various mucin-like threonine/serine-rich repeats. Phylogenetic analysis indicated the close relationship between this gene and the submaxillary mucin from porcine and bovine. A polydispersed signal was observed on the Northern blot, which indicates very large mRNA size. Further analysis of the upstream genomic sequences generated from human and mouse genome projects revealed three additional vWF D domains and many mucin-like threonine/serine-rich repeats. The expression of this gene is restricted to the mucous cells of various glandular tissues, including sublingual gland, submandibular gland, and submucosal gland of the trachea. Based on the chronological convention, we have given the name MUC19 to the human ortholog and Muc19 to the mouse.

Regulation of Airway Mucin Gene Expression

“…MUC19 is a recently identified secreted gel-forming mucin. Its expression is localized mainly to the mucous cells of the salivary glands and submucosal glands of the trachea (138). The extent to which MUC19 secretion is significant to airway mucus rheology remains to be defined.…”

The Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

“…To investigate whether PGD 2 induced MUC5B gene expression in a time-dependent manner, we performed RT-PCR after treating NCI-H292 cells with 1 M PGD 2 for various times (1,3,6,12, and 24 h). We observed a time-dependent increase in expression of MUC5B in NCI-H292 cells over a 24-h time period (greater than 2-fold increase) (Fig.…”

Assay of mucins in human tear fluid

“…Mucins are defined as glycoproteins, hydrophilic in nature, that have at least 50-80% of their mass as carbohydrate, O-linked to serine and threonine residues present within tandem repeats of amino acids in their protein backbone (Gendler and Spicer, 1995;Moniaux et al, 2001;Hollingsworth and Swanson, 2004). To date, at least 20 distinct human mucin genes have been cloned (Gendler and Spicer, 1995;Lapensee et al, 1997;Williams et al, 1999;Williams et al, 2001;Yin and Lloyd, 2001;Gum et al, 2002;Pallesen et al, 2002;Chen et al, 2004;Higuchi et al, 2004;Hollingsworth and Swanson, 2004). Of these, MUCs 1, 3A, 3B, 4, 12, 13, 15, 16, 17 and 20 have been characterized as membrane associated.…”