Biosynthesis of human colonic mucin: Muc2 is the prominent secretory mucin

Tytgat, Kristien M. A. J.; Büller, Hans A.; Opdam, Frank J.M.; Kim, Young S.; Einerhand, Alexandra W. C.; Dekker, Jan

doi:10.1016/0016-5085(94)90537-1

Cited by 227 publications

(213 citation statements)

References 39 publications

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“…In addition, the following histochemical and immunohistochemical staining was also performed: galactose oxidase-Schiff (GOS), paradoxical ConA, immunostaining with mAb 45M1 (Novocastra) (Bara et al, 1991), immunostaining with MUC 2 mAb (Novocastra) (Tytgat et al, 1994), and immunostaining with CD10 mAb (Novocastra) (Danielsen et al, 1980). Galactose oxidase-Schiff and 45M1 were used to detect gastric foveolar mucin, ConA to detect pyloric-gland cells and mucous neck cells, MUC 2 to detect intestinal gobletcell mucin, and CD10 to detect brush borders in complete-type intestinal metaplasia.…”

Section: Cellular Phenotypic Analysismentioning

confidence: 99%

Molecular and Cellular Phenotypic Profiles of Gastric Noninvasive Neoplasia

Jin

Tamura

Honda

et al. 2002

Laboratory Investigation

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SUMMARY:According to the Padova international classification, 52 gastric noninvasive neoplasias (NIN) were classified as follows: 20 low-grade NIN (L-NIN); 9 high-grade NIN including suspicion for carcinoma without invasion (H-NIN); and 23 high-grade NIN including carcinoma without invasion (Ca-NIN). The molecular and cellular phenotypic profiles were investigated and compared. The APC gene was mutated in seven (35%) L-NIN, two (22%) H-NIN, and two (9%) Ca-NIN tumors; APC mutations were significantly more frequent in L-NIN compared with Ca-NIN tumors (p Ͻ 0.05). Mutations of the p53 gene were found in five (22%) Ca-NIN tumors but were not observed in L-NIN or H-NIN tumors (p Ͻ 0.05). Loss of heterozygosity involving at least one chromosomal locus was detected in 14 (61%) Ca-NIN tumors but was not detected in L-NIN or H-NIN tumors. High-frequency microsatellite instability (MSI-H) was detected in one (5%) L-NIN tumor and in six (26%) Ca-NIN tumors. The frequencies of loss of heterozygosity and MSI-H were significantly higher in Ca-NIN than in L-NIN or H-NIN tumors (p Ͻ 0.05). Nuclear accumulation of p53 protein was detected in no L-NIN tumors, 1 (11%) H-NIN tumor, and 10 (44%) Ca-NIN tumors (p Ͻ 0.01). All tumors with loss of hMLH1 expression exhibited MSI-H (p Ͻ 0.01). Cellular phenotypic analysis revealed that seven (35%) L-NIN tumors and one (4%) Ca-NIN tumor had complete-type intestinal metaplastic phenotype and that one (5%) L-NIN tumor and one (4%) Ca-NIN tumor had a gastric foveolar epithelial phenotype, whereas the remaining tumors exhibited an ordinary phenotype. Thus, the complete-type intestinal metaplastic phenotype was more characteristic of L-NIN tumors than of H-NIN or Ca-NIN tumors (p Ͻ 0.01). In summary, the Padova international classification correlated with both the molecular and cellular phenotypic profiles. In practice, p53 and hMLH1 immunohistochemistry discriminated Ca-NIN from L-NIN and H-NIN tumors. (Lab Invest 2002, 82:1637-1645.

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Section: Cellular Phenotypic Analysismentioning

confidence: 99%

Molecular and Cellular Phenotypic Profiles of Gastric Noninvasive Neoplasia

Jin

Tamura

Honda

et al. 2002

Laboratory Investigation

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“…The mucus layer is composed of mucins and one secretory mucin in particular, Muc2, is abundantly expressed in human, rat and mouse colonic epithelium. [9][10][11][12][13] We recently found that intestinal loss of Muc2, affecting the protective capacities of the mucus layer, leads to colonic inflammation in mice. 14 Furthermore, the activity of mucosal inflammation in human UC correlates significantly with lowered MUC2 synthesis and secretion.…”

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confidence: 99%

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Sluis

Bouma

Vincent

et al. 2008

Laboratory Investigation

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Expression of the mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10 À/À ) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10 DKO ) mice were characterized and compared to Muc2 knockout (Muc2 À/À ), IL-10 À/À and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the proinflammatory cytokines in colonic tissue and serum were determined. IL-10 À/À mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10 DKO and Muc2 À/À mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10 DKO mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10 DKO mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10 DKO mice. In conclusion, Muc2/IL-10 DKO mice develop colitis, which is more severe in every aspect compared to Muc2 À/À and IL-10 À/À mice. These data indicate that (i) in case of Muc2 deficiency, the antiinflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.

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“…MUC2, the major mucin secreted by human colonic goblet cells [1], and MUC5AC, which is secreted by the surface mucous cells of the human stomach [2], are both large oligomeric glycoproteins which can be reduced to their monomeric constituents by interchain-disulphide-bond cleavage. They are heavily O-glycosylated, with most oligosaccharide chains being O-linked to threonine and serine residues in the central tandemrepeat regions of the polypeptide core [3].…”

Section: Introductionmentioning

confidence: 99%

“…In agreement with this hypothesis, it has been Abbreviations used : ER, endoplasmic reticulum ; CRT, calreticulin ; CLN, calnexin ; EMEM, Eagle's minimum essential medium ; endo H, endo β-Nacetylglucosaminidase ; TUN, tunicamycin ; CAS, castanospermine ; PDI, protein disulphide-isomerase ; CHO, Chinese-hamster ovary. 1 To whom correspondence should be addressed (e-mail gforst!sickkids.on.ca) MUC2 was completely oligomerized and was endo-β-Nacetylglucosaminidase-resistant, indicating that the mucin had reached the Golgi region. MUC2 co-precipitated with CRT at zero time and 0.5 h was endo-β-N-acetylglucosaminidasesensitive ; therefore CRT must have associated with MUC2 in the ER.…”

Section: Introductionmentioning

confidence: 99%

“…Potential N-glycosylation sites are also located in the N-and Cterminal regions, and some are known to be occupied, since monomeric precursors of both MUC2 and MUC5AC contain Nglycans [1,2]. From radiolabelled-amino-acid pulse-chase studies, using explants of normal human colon [1] and cultures of colonic adenocarcinoma cells [11,12], it is clear that MUC2 is initially synthesized in the endoplasmic reticulum (ER) as a monomeric precursor which migrates with an apparent molecular mass of approx. 600 000 Da on SDS\PAGE.…”

Section: Introductionmentioning

confidence: 99%

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Roles of calreticulin and calnexin during mucin synthesis in LS180 and HT29/A1 human colonic adenocarcinoma cells

McCool

Okada

Forstner

et al. 1999

Biochemical Journal

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Molecular chaperones are presumed to associate with large secretory mucin glycoproteins during their synthesis in the endoplasmic reticulum (ER), but have not been identified to date. We decided to look for possible involvement of the chaperones calreticulin (CRT) and calnexin (CLN) during synthesis of two similar gastrointestinal mucins, MUC2 and MUC5AC. Pulse-chase labelling of MUC2 and MUC5AC with [$&S]methionine\cysteine ([$&S]Promix) was performed using LS180 and HT29\A1 colonic carcinoma cell lines and was followed by immunoprecipitation with anti-mucin and antichaperone antibodies. The precipitated labelled mucin precursors were analysed by SDS\PAGE and autoradiography. Using antibodies specific for each mucin, newly synthesized monomeric precursors of both MUC2 and MUC5AC were detected after a 15 min pulse and then disappeared as oligomers were formed during a 2 h chase period. Only homo-oligomers of MUC2 and MUC5AC were present in the cells. Using anti-CRT, the MUC2 monomeric precursor and oligomer were co-precipitated from both cell lines after a 15 min pulse and the oligomer less strongly after a 0.5 h chase, but there was little co-precipitation after a 2 h chase. At this time, MUC2 immunoprecipitated by anti-

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Biosynthesis of human colonic mucin: Muc2 is the prominent secretory mucin

Cited by 227 publications

References 39 publications

Molecular and Cellular Phenotypic Profiles of Gastric Noninvasive Neoplasia

Molecular and Cellular Phenotypic Profiles of Gastric Noninvasive Neoplasia

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Roles of calreticulin and calnexin during mucin synthesis in LS180 and HT29/A1 human colonic adenocarcinoma cells

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