Alternative splicing of the human MUC2 gene

Sternberg, Lawrence R.; Byrd, James C.; Hansson, Gunnar C.; Liu, Kai Feng; Bresalier, Robert S.

doi:10.1016/j.abb.2003.10.002

Cited by 12 publications

(10 citation statements)

References 43 publications

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“…In MUC2 -MS5 and -MS8 (introns 26 and 40, respectively) we also found several canonical CACGT-binding sites for the MYC family of oncogenic transcription factors. Furthermore, alternatively-spliced transcript variants of MUC2 that include variations in intron 30 and exon 30 have been described previously [32]. Therefore, our data suggest that these minisatellites may contain sequences that are involved in two major regulatory mechanisms for MUC2 : transcriptional control of MUC2 and alternative splicing of MUC2 transcripts.…”

Section: Discussionsupporting

confidence: 67%

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

et al. 2007

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BackgroundMucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer.Methodology/Principle FindingsWe analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455), colon (192) and rectal (271) cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31–5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44) and long (47, 50 and 54), according to their TR (tandem repeats) lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93–16.42; p = 0.00036). Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement.Conclusions/SignificanceOur observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells.

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Section: Discussionsupporting

confidence: 67%

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

et al. 2007

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“…While the repression and overexpression that we produced could have been achieved by using combinations of several siRNAs or cDNAs, these methods are limited. For example, in various tumor cell lines, alternatively spliced variants of oncogenic proteins have been observed (21,37,66,67). Alternatively spliced ErbB2 proteins have been shown to mediate effects that differ from those of the full-length receptor protein (2,62,82).…”

Section: Discussionmentioning

confidence: 99%

Zinc Finger Transcription Factors Designed for Bispecific Coregulation of ErbB2 and ErbB3 Receptors: Insights into ErbB Receptor Biology

Lund

Popkov

Magnenat

et al. 2005

Molecular and Cellular Biology

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Signaling through the ErbB family of tyrosine kinase receptors in normal and cancer-derived cell lines contributes to cell growth and differentiation. In this work, we altered the levels of ErbB2 and ErbB3 receptors, individually and in combination, by using 6-finger and 12-finger synthetic zinc finger protein artificial transcription factors (ATFs) in an epidermoid squamous cell carcinoma line, A431. We successfully designed 12-finger ATFs capable of coregulating ErbB3 and ICAM-1 or ErbB2 and ErbB3. With ATFs, the effects of changes in ErbB2 and ErbB3 receptor levels were evaluated by using cell proliferation, cell migration, and cell signaling assays. Cell proliferation was increased when ErbB2 and ErbB3 were both overexpressed. Cell migration on collagen was decreased when ErbB2 was down-regulated, yet migration on laminin was significantly increased with ErbB3 overexpression. ErbB2 and ErbB3 overexpression also stimulated the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Our ATF approach has elucidated differences in ErbB receptor-mediated proliferation, migration, and intracellular signaling that cannot be explained merely by the presence or absence of particular ErbB receptors and emphasizes the dynamic nature of the ErbB signaling system. The transcription factor approach developed here provides a gene-economical route to the regulation of multiple genes and may be important for complex gene therapies.Signaling from ErbB tyrosine kinase receptors influences diverse aspects of a cell's biology that include growth, differentiation, migration, and apoptosis (29, 84). ErbB1 (EGFR/ HER1) was the first member of the family identified. Based on homology to ErbB1, three additional family members, ErbB2 (HER2/p185), ErbB3 (HER3), and ErbB4 (HER4), were identified (41,56,60,77). In normal development, binding of a growth factor ligand induces dimerization of ErbB receptors. Subsequently, the cytoplasmic tails are transphosphorylated. Each ErbB receptor has a unique pattern of phosphorylation sites that recruit various secondary signaling proteins (23,51,52,55,71). Ongoing research shows that the identity of the ligand bound, the amount of ligand, and the identities of dimers formed determine the activation of a particular intracellular signaling pathway such as the mitogen-activated protein kinase (MAPK), the stress-activated protein kinase, the protein kinase C, or the Akt pathway (53,61,72). The combination of at least 10 different ligands and 10 possible receptor dimers of the ErbB system form a signaling network essential for development (15,34).Various cancers, including those of the breast, head and neck, kidney, prostate, colon, pancreas, bladder, lung, and ovaries, are associated with overexpression of ErbB receptors (11,59,84). Research using breast cancer models has identified a dominant role for ErbB2 in tumor cell proliferation and metastasis (35,64,73,74). ErbB2 is the preferred dimerization partner for all ErbB receptors, and dimers containing ErbB2 have higher ligand af...

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“…In addition, analysis of MUC2 in the LS174T derived HM7 colon cancer cell line led to the identification of a transcript variant that lacked the second PTS domain [20]. The presence of this highly polymorphic PTS VNTR (variable number of tandem repeats) has inhibited the resolution of the full-length mRNA, as well as the functional annotation of the complete DNA sequence in many species, including mouse and human [4], [9], [10].…”

Section: Introductionmentioning

confidence: 99%

Cloning, Annotation and Developmental Expression of the Chicken Intestinal MUC2 Gene

2013

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Intestinal mucin 2 (MUC2) encodes a heavily glycosylated, gel-forming mucin, which creates an important protective mucosal layer along the gastrointestinal tract in humans and other species. This first line of defense guards against attacks from microorganisms and is integral to the innate immune system. As a first step towards characterizing the innate immune response of MUC2 in different species, we report the cloning of a full-length, 11,359 bp chicken MUC2 cDNA, and describe the genomic organization and functional annotation of this complex, 74.5 kb locus. MUC2 contains 64 exons and demonstrates distinct spatiotemporal expression profiles throughout development in the gastrointestinal tract; expression increases with gestational age and from anterior to posterior along the gut. The chicken protein has a similar domain organization as the human orthologue, with a signal peptide and several von Willebrand domains in the N-terminus and the characteristic cystine knot at the C-terminus. The PTS domain of the chicken MUC2 protein spans ∼1600 amino acids and is interspersed with four CysD motifs. However, the PTS domain in the chicken diverges significantly from the human orthologue; although the chicken domain is shorter, the repetitive unit is 69 amino acids in length, which is three times longer than the human. The amino acid composition shows very little similarity to the human motif, which potentially contributes to differences in the innate immune response between species, as glycosylation across this rapidly evolving domain provides much of the musical barrier. Future studies of the function of MUC2 in the innate immune response system in chicken could provide an important model organism to increase our understanding of the biological significance of MUC2 in host defense and highlight the potential of the chicken for creating new immune-based therapies.

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Alternative splicing of the human MUC2 gene

Cited by 12 publications

References 43 publications

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

Zinc Finger Transcription Factors Designed for Bispecific Coregulation of ErbB2 and ErbB3 Receptors: Insights into ErbB Receptor Biology

Cloning, Annotation and Developmental Expression of the Chicken Intestinal MUC2 Gene

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