Human Mucin Genes Assigned to 11p15.5: Identification and Organization of a Cluster of Genes

Pigny, Pascal; Guyonnet‐Duperat, Véronique; Hill, Alexander S.; Pratt, Wendy S.; Galiègue‐Zouitina, Sylvie; d’Hooge, Maud Collyn; Laine, Anne; Seuningen, Isabelle Van; Degand, Pierre; Gum, James R.; Kim, Young S.; Swallow, Dallas M.; Aubert, Jean‐Pierre; Porchet, Nicole

doi:10.1006/geno.1996.0637

Cited by 203 publications

(159 citation statements)

References 5 publications

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“…The MUC5B locus is clustered on chromosome 11p15.5 with genes encoding the secreted MUC6, MUC2 and MUC5AC secreted mucins (41). Based on genomic organization, sequence similarities and their ordering on chromosome 11, the evidence indicates that these four genes evolved from a common progenitor (42,43).…”

Section: Muc1-n Sequences Also Evolved From the Secreted Mucinsmentioning

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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Section: Muc1-n Sequences Also Evolved From the Secreted Mucinsmentioning

confidence: 99%

Evolution of the human MUC1 oncoprotein

Duraisamy¹,

Kufe²,

Ramasamy³

et al. 2007

Int J Oncol

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“…These four genes are located within a 400-kb long cluster, on the p15.5 region of chromosome 11 (Pigny et al, 1996) in an area known to be a hot spot of abnormal methylation in cancer (De Bustros et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…Having previously found that these genes were located in a hot spot of methylation in the genome (Pigny et al, 1996), that their pattern of expression was altered in epithelial cancers (Copin et al, 2001;Van Seuningen et al, 2001) and that their promoters were GC-rich (Van Seuningen et al, 2001), we undertook to investigate, in the same study, the importance of not only DNA methylation but also the influence of histone modifications for each gene of the cluster and propose key CpG sites that could be used as valuable markers in epithelial cancers. To our knowledge, this is the first time that such a question is investigated simultaneously for the four genes.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells

et al. 2007

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The human genes MUC2, MUC5AC, MUC5B and MUC6 are clustered on chromosome 11 and encode large secreted gel-forming mucins. The frequent occurrence of their silencing in cancers and the GC-rich structure of their promoters led us to study the influence of epigenetics on their expression. Pre-and post-confluent cells were treated with demethylating agent 5-aza-2 0 -deoxycytidine and histone deacetylase (HDAC) inhibitor, trichostatin A. Mapping of methylated cytosines was performed by bisulfite-treated genomic DNA sequencing. Histone modification status at the promoters was assessed by chromatin immunoprecipitation assays. Our results indicate that MUC2 was regulated by site-specific DNA methylation associated with establishment of a repressive histone code, whereas hypermethylation of MUC5B promoter was the major mechanism responsible for its silencing. DNA methyltransferase 1 was identified by small interfering RNA approach as a regulator of MUC2 and MUC5B endogenous expression that was potentiated by HDAC2. MUC2 and MUC5B epigenetic regulation was cellspecific, depended on cell differentiation status and inhibited their activation by Sp1. The expression of MUC5AC was rarely influenced by epigenetic mechanisms and methylation of MUC6 promoter was not correlated to its silencing. In conclusion, this study demonstrates the important role for methylation and/or histone modifications in regulating the 11p15 mucin genes in epithelial cancer cells.

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“…All but MUC19 are encoded by genes present in a cluster on chromosome 11p15. 13 MUC2 is the predominant secreted mucin synthesized by colonic goblet cells, 14 along with MUC5B. 15 In the normal colon, MUC5AC is rarely expressed, and only by a minority of goblet cells, and there are conflicting reports concerning the expression of MUC6 in the colon.…”

mentioning

confidence: 99%

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

et al. 2013

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Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (425% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all Po0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.

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Human Mucin Genes Assigned to 11p15.5: Identification and Organization of a Cluster of Genes

Cited by 203 publications

References 5 publications

Evolution of the human MUC1 oncoprotein

Evolution of the human MUC1 oncoprotein

Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

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