Disease relevance of Dmbt1

• The mucinlike glycoprotein MUCLIN, one of two protein products of the CRP-ductin gene, was used to study changes in the expression of sulfated glycoconjugates during the pathogenesis of cystic fibrosis, using the cystic fibrosis transmembrane conductance regulator (CFTR) knockout mouse (CF mouse) [1].
• We conclude that CRP-ductin is the mouse homologue of human gp-340 and that its capacity to bind SP-D as well as gram-negative and gram-positive bacteria suggests a role in mucosal immune defense [2].
• Other proteins known to have these domains include CRP-ductin, a cDNA expressed at high levels in mouse intestine (8 SRCR, 5 CUB, 1 ZP), ebnerin, a protein cloned from a rat taste bud library (4 SRCR, 3 CUB, 1 ZP), and DMBT1, a sequence in human chromosome 10q25-26 frequently deleted in malignant gliomas (9 SRCR, 2 CUB, 1 ZP) [3].
• We examined the expression of galectin-3 in the rabbit kidney and its relationship to hensin during metabolic acidosis [4].

High impact information on Dmbt1

• RESULTS: MUCLIN is expressed in the normal mouse intestinal tract, pancreas, and gallbladder [5].
• In the CFTR knockout mouse duodenum and gallbladder, MUCLIN showed retarded electrophoretic migration indicating altered posttranslational processing [5].
• In the duodenum, MUCLIN was localized intracellularly in crypt enterocytes and on the luminal surface, and luminal surface labeling was dramatically increased in the CFTR knockout mouse [5].
• Here, we show that mouse embryonic stem cells seeded on hensin or laminin, but not fibronectin or collagen type IV, formed hemispheric epithelial structures whose outermost layer terminally differentiated to an epithelium that resembled the visceral endoderm [6].
• These expression patterns, and the fact that hensin null embryos (and those already reported for laminin) die at the onset of egg cylinder formation, support the view that hensin and laminin are required for terminal differentiation of columnar and squamous epithelial phenotypes during early embryogenesis [6].

Biological context of Dmbt1

• In both organs, MUCLIN labeling of the luminal surface was increased concomitantly with dilation and protein or mucus plugging but before upregulation of expression [1].
• Sequence homologies indicate that CRP-ductin is the mouse homologue of human gp-340, a glycoprotein that agglutinates microorganisms and binds the lung mucosal collectin surfactant protein-D (SP-D) [2].
• Expression of sulfated gp300 and changes in glycosylation during pancreatic development [7].
• A prediction of this proposed function is that gp300 expression should be coordinately regulated with the digestive enzymes and appearance of zymogen granules during differentiation of acinar cells in fetal development [7].
• Hensin may participate in determining the polarized phenotype of other epithelia and brain cells [3].

Anatomical context of Dmbt1

• In CFTR knockout mice, MUCLIN shows increased expression at both mRNA and protein levels in pancreas and duodenum, but not in the gallbladder [5].
• We assessed the appearance of dilated lumina containing protein or mucus plugs in pancreatic acini and crypts of the small intestine and quantified MUCLIN protein and CRP-ductin mRNA during postnatal development [1].
• CRP-ductin is a protein expressed mainly by mucosal epithelial cells in the mouse [2].
• The pancreas was the main site of synthesis of CRP-ductin, but transcripts were also readily amplified from salivary gland, the gastrointestinal tract, liver, testis, uterus and lung [2].
• In situ hybridization analysis shows strong expression of vomeroglandin mRNA in the glands of vomeronasal system [8].

Associations of Dmbt1 with chemical compounds

• Developmental expression of a mucinlike glycoprotein (MUCLIN) in pancreas and small intestine of CF mice [1].
• Similarly, intestinal crypts had CF-like mucus plugs by P16, but MUCLIN protein was first elevated by P23 and remained elevated through adulthood compared with normal mice [1].
• Non-sulfated [35S]Met/Cys-labeled Muclin showed decreased binding in the overlay assay [9].
• Denaturation of Muclin with reducing agents to break the numerous intrachain disulfide bonds in Muclin's scavenger receptor cysteine-rich and CUB domains did not interfere with binding [9].
• Here we report that purified CRP-ductin binds human SP-D in a calcium-dependent manner and that the binding is not inhibited by maltose [2].

Physical interactions of Dmbt1

• The behavior of Muclin fulfils the requirement of a Golgi cargo receptor to bind to regulated secretory proteins under the mildly acidic pH conditions that exist in the trans-Golgi network [9].

Other interactions of Dmbt1

• The pancreatic zymogen granule membrane protein gp300 is the major sulfated glycoprotein of the mouse acinar cell and has been proposed to be an important structural component of the zymogen granule membrane [7].
• Using intercalated cells in culture, we found that galectin-3 facilitated hensin polymerization, thereby causing their differentiation into the H+-secreting cell phenotype [4].
• With supramaximal cerulein stimulation, vacuoles formed which contained Muclin, amylase, and LAMP1 [10].
• Treatment of dual-labeled gp300 with PNGase F to cleave N-linked oligosaccharides released approximately 17% of [3H] and little [35S] [11].
• Bacterial survival is associated with increased expression of muclin and sprr2a in the intestine, indicating that these genes play protective roles in the intestine [12].

Analytical, diagnostic and therapeutic context of Dmbt1

• METHODS: Western and Northern blots were used to determine the tissue levels of MUCLIN and its messenger RNA (mRNA) in normal and CFTR knockout mice [5].
• Immunocytochemistry was used to determine the localization of MUCLIN [5].
• A polyclonal antibody raised against gp-340 reacted specifically with CRP-ductin in Western blots [2].
• Sulfate on gp300 is resistant to hot 1N HCl, but sensitive to alkaline hydrolysis, demonstrating that the sulfate is carbohydrate-linked rather than tyrosine-linked. gp300 metabolically labeled with [3H]glucosamine and [35S]sulfate was chemically and enzymatically treated followed by Bio-Gel P-10 gel filtration [11].

References