The MUC family: an obituary

Dekker, Jan; Rossen, John W. A.; Büller, Hans A.; Einerhand, Alexandra W. C.

doi:10.1016/s0968-0004(01)02052-7

Cited by 344 publications

(289 citation statements)

References 35 publications

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“…Regulation pathways of MUC gene expression have recently been examined, but are still a matter of debate. First, the chromosomal localization of MUC genes could help in understanding their different modulations; MUC3 is located on the chromosome 7q22, whereas MUC2, MUC5AC, and MUC5B belong to a cluster located on the chromosome 11p15.5, probably originating from an ancestral gene and possibly sharing pathways of regulation (15). Second, our demonstration that TSA reproduces the effects of butyrate only on the MUC3 gene suggests that HDAC inhibition can be involved in the action of butyrate on MUC3 expression but not on MUC2, MUC5AC, and MUC5B gene expressions.…”

Section: Discussionmentioning

confidence: 99%

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Butyrate specifically modulatesMUCgene expression in intestinal epithelial goblet cells deprived of glucose

Gaudier

Jarry²,

Blottière³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

283

176

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The mucus layer covering the gastrointestinal mucosa is considered the first line of defense against aggressions arising from the luminal content. It is mainly composed of high molecular weight glycoproteins called mucins. Butyrate, a shortchain fatty acid produced during carbohydrate fermentation, has been shown to increase mucin secretion. The aim of this study was to test 1) whether butyrate regulates the expression of various MUC genes, which are coding for protein backbones of mucins, and 2) whether this effect depends on butyrate status as the major energy source of colonocytes. Butyrate was provided at the apical side of human polarized colonic goblet cell line HT29-Cl.16E in glucose-rich or glucose-deprived medium. In glucose-rich medium, butyrate significantly increased MUC3 and MUC5B expression (1.6-fold basal level for both genes), tended to decrease MUC5AC expression, and had no effect on MUC2 expression. In glucose-deprived medium, i.e., when butyrate was the only energy source available, MUC3 and MUC5B increase persisted, whereas MUC5AC expression was significantly enhanced (3.7-fold basal level) and MUC2 expression was strikingly increased (23-fold basal level). Together, our findings show that butyrate is able to upregulate colonic mucins at the transcriptional level and even better when it is the major energy source of the cells. Thus the metabolism of butyrate in colonocytes is closely linked to some of its gene-regulating effects. The distinct effects of butyrate according to the different MUC genes could influence the composition and properties of the mucus gel and thus its protective function. mucin; short-chain fatty acids; energy source; human colonic cell line THE MUCUS LAYER, COVERING the gastrointestinal mucosa, is considered the first line of defense against mechanical, chemical, or microbiological aggressions arising from the luminal contents (14). Mucus is mostly composed of mucins, i.e., glycoproteins of high molecular weight, whose protein backbones are encoded by MUC genes. So far, at least 15 different MUC genes have been identified in humans (15,32). In the large intestinal mucosa, the main MUC genes are MUC2, and to a lesser extent MUC1, MUC3, and MUC4. MUC2 codes for the main secreted mucin in the colon, whereas MUC1, MUC3, and MUC4 mainly code for membrane-located mucins but also present splicing variants coding for secreted mucins (50). Apart from their gel-forming protective function, some membrane-linked mucins, such as MUC1 (22) and MUC4 (12), exhibit specific functions in adhesion and cell signaling.MUC gene expression is altered in many colonic diseases. MUC2 is overexpressed in mucinous colorectal carcinoma, whereas its expression is particularly low in nonmucinous carcinoma (17, 43). MUC5AC and MUC6 expressions are abnormally induced in colon adenoma (6, 9). Aberrant expression of MUC genes (8) as well as modifications of their transcription (34, 45) have also been observed in inflammatory bowel disease. In addition, the thickness of the mucus layer is reduced in ulce...

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Section: Discussionmentioning

confidence: 99%

“…Mucus is mostly composed of mucins, i.e., glycoproteins of high molecular weight, whose protein backbones are encoded by MUC genes. So far, at least 15 different MUC genes have been identified in humans (15,32). In the large intestinal mucosa, the main MUC genes are MUC2, and to a lesser extent MUC1, MUC3, and MUC4.…”

mentioning

confidence: 99%

Butyrate specifically modulatesMUCgene expression in intestinal epithelial goblet cells deprived of glucose

Gaudier

Jarry²,

Blottière³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

283

176

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“…However, no information is available regarding the origin of the MUC1-C extracellular and cytoplasmic domains. The mucins are classified in the same family based on the presence of an extensively O-glycosylated tandem repeat structure, rather than a common genetic origin (24). Thus, with the exception of the SEA domain, MUC1 has no sequence similarity with the other membrane-bound mucins (25).…”

Section: Discussionmentioning

confidence: 99%

“…The MUC family members have been grouped according to a biophysical structure rather than having evolved from common ancestral genes (24). In this regard, a recent analysis has shown that MUC1 homologs are restricted to mammalian species (25).…”

Section: Introductionmentioning

confidence: 99%

Evolution of the human MUC1 oncoprotein

Duraisamy¹,

Kufe²,

Ramasamy³

et al. 2007

Int J Oncol

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Abstract. The mucin (MUC) family consists of secreted and membrane-bound forms. The transmembrane mucin 1 (MUC1) is a heterodimer that is aberrantly overexpressed by diverse human carcinomas and certain hematologic malignancies. The MUC1 N-terminal (MUC1-N) and C-terminal (MUC1-C) subunits are generated by autocleavage within a SEA domain. The MUC1 cytoplasmic domain (MUC1-CD) located downstream of the SEA domain is sufficient for the induction of anchorage-independent growth and tumorigenicity; however, no information is available regarding the origin of these transforming sequences. Previous work demonstrated that, except for the SEA domain, MUC1 has no sequence homology with other membrane-bound mucins. The present results demonstrate that MUC1-CD evolved from repeat regions in the MUC5B secreted mucin. We also show that MUC1 sequences upstream to the SEA domain emerged from MUC5B. These findings indicate that both the MUC1-N and MUC1-C subunits evolved from secreted gel-forming mucins and that the MUC1-CD oncogenic function emerged by diversification after evolution from MUC5B.

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“…12 MUC5AC and MUC6, which are located on chromosome 11p15, demonstrate considerably similar overall homologies. 12 MUC5AC is predominantly expressed in gastric foveolar epithelial cells and is considered to be a major gastric mucin. MUC6 is also expressed in the gastric pyloric glands.…”

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confidence: 99%

Prognostic significance of CDX2 and mucin expression in small intestinal adenocarcinoma

et al. 2014

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The clinicopathological and prognostic significance of CDX2 and mucin expression have not been comprehensively evaluated in small intestinal adenocarcinoma. Immunohistochemical microarray analyses of CDX2, MUC1, MUC5AC, and MUC6 protein expressions in 189 surgically resected small intestinal adenocarcinoma cases were examined and compared with various clinicopathologic variables, including survival. CDX2, MUC1, MUC5AC, and MUC6 expressions were observed in 43.4% (82 patients), 37.6% (71), 31.7% (60), and 21.7% (41) of patients, respectively. Whereas CDX2 expression was found to be associated with lowgrade tumors (P ¼ 0.034), fewer nodal metastases (P ¼ 0.019), and less perineural invasion (P ¼ 0.049) in small intestinal adenocarcinoma patients, patients expressing MUC1 tended to demonstrate high-grade (P ¼ 0.021) and nodular or infiltrative (P ¼ 0.020) tumors. On the basis of the combined CDX2, MUC1, MUC5AC, and MUC6 expression patterns, small intestinal adenocarcinoma patients were further classified as intestinalAmong these immunophenotypes, intestinal-type patients demonstrated more frequent distal (jejunal or ileal; P ¼ 0.033), tubular (P ¼ 0.039), and low-grade tumors (P ¼ 0.004) and significantly better survival according to univariate (Po0.0001) and multivariate (P ¼ 0.001) analyses. In summary, intestinal immunophenotype adenocarcinomas are associated with distal (jejunal or ileal), tubular, and low-grade tumors and better survival outcomes. Hence, CDX2 and mucin immunohistochemical staining may provide better estimations of survival after surgical resection and intestinal immunophenotype could therefore be used as a better prognostic indicator of small intestinal adenocarcinoma. Modern Pathology (2014Pathology ( ) 27, 1364Pathology ( -1374 doi:10.1038/modpathol.2014 published online 7 March 2014 Keywords: adenocarcinoma; CDX2; immunohistochemistry; mucin; prognosis; small intestine Primary small intestinal adenocarcinomas account for only 5% of malignant neoplasms in the gastrointestinal tract despite the long length of the small intestine and the significant mucosal coverage over the entire gastrointestinal tract. 1 In 2013, it is estimated that 8810 Americans will be diagnosed with small intestinal adenocarcinoma. 1 Despite recent improvements in the detection of the small intestinal adenocarcinomas, including improved imaging techniques and endoscopic modalities, the diagnosis of small intestinal adenocarcinomas is usually made at an advanced clinical stage and the 5-year survival rate is only 41.2%. 2 Several clinicopathologic factors, including lymph node metastasis and the distal locations of these tumors (jejunum and ileum), are known as the most important independent prognostic factors. 2 Although several molecular alterations, including KRAS, TP53, and DPC4/SMAD4 mutations and the overexpression of cyclinD1, are known to be involved in small intestinal adenocarcinoma carcinogenesis, [3][4][5][6]

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The MUC family: an obituary

Cited by 344 publications

References 35 publications

Butyrate specifically modulatesMUCgene expression in intestinal epithelial goblet cells deprived of glucose

Butyrate specifically modulatesMUCgene expression in intestinal epithelial goblet cells deprived of glucose

Evolution of the human MUC1 oncoprotein

Prognostic significance of CDX2 and mucin expression in small intestinal adenocarcinoma

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