Disease relevance of Muc2

• We found that inactivation of p21(WAF1/cip1) significantly increased the frequency and size of intestinal tumors in Muc2 knockout mice and also led to development of more invasive adenocarcinomas [1].
• Muc2 gene expression was not modified by colitis, whereas Muc3 gene expression was increased (x2) only in the cecum and the distal colon of mice after acute colitis [2].
• Thus, Muc2 is involved in the suppression of colorectal cancer [3].
• Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis [4].
• In this report, we first investigated the state of mucous cell metaplasia and the mechanisms by which MCM is reduced despite continued exposures to allergen [5].

High impact information on Muc2

• Analyses of the mucins Muc2, Muc3, and Muc5ac showed lower levels of RNA expression in the CF mice and similar levels of protein [6].
• Colonic goblet cells in the Muc2(-/-) mice were negative for Muc2, but trefoil factor 3 was still detectable [7].
• Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection [7].
• There was also decreased goblet cell differentiation as assessed by alcian blue staining and expression of the Muc2 gene, especially in mice fed the Western-style diet, although this differentiation lineage was still present as indicated by expression and staining for intestinal trefoil factor [8].
• However, Klf4(-/-) mice demonstrate a 90% decrease in the number of goblet cells in the colon, show abnormal expression of the goblet cell-specific marker Muc2 by in situ hybridization, have abnormal staining of the colonic epithelium with Alcian Blue for acidic mucins, and lack normal goblet cell morphology by ultrastructural analysis [9].

Chemical compound and disease context of Muc2

• Mucositis was induced in Muc2 knockout (Muc2(-/-)) and wild type (Muc2(+/+)) mice by injecting methotrexate (MTX) [4].

Biological context of Muc2

• This gene is clustered with the three secreted large gel-forming mucins Muc2, Muc5ac, and Muc5b in a region that exhibits synteny with human chromosome 11p15 [10].
• RESULTS: Antibiotic treatment did not significantly affect Muc2 and Muc3 gene expression in CF mice [11].
• The murine Muc2 mucin gene is transcriptionally regulated by the zinc-finger GATA-4 transcription factor in intestinal cells [12].
• Four GATA-4 cis-elements were identified in the promoter by EMSA and Muc2 promoter was efficiently activated when GATA-4 was overexpressed in the cells with a loss of transactivation when those sites were either mutated or a mutated form of GATA-4 was used [12].
• Having found putative GATA binding sites in the murine Muc2 promoter and that GATA-4 is expressed in Muc2-expressing goblet cells of the mouse small intestine, we undertook to study its regulation by this transcription factor [12].

Anatomical context of Muc2

• Muc2(-/-) mice develop tumors in the small and large intestine and the rectum, but in contrast to tumors in Apc1638(+/-) mice, this does not involve increased expression or nuclear localization of beta-catenin [1].
• A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment [4].
• These quantitative and structural aberrations in Muc2 in IL-10 mice likely reduce the ability of their mucosa to cope with nonpathogenic commensal bacteria and may contribute to their susceptibility to develop colitis [13].
• To help us investigate the role of mucin in the protection of the colonic epithelium in the mouse, we aimed to identify the murine colonic mucin (MCM) and its encoding gene [14].
• We isolated MCM, raised an anti-MCM antiserum, and studied the biosynthesis of MCM in the gastrointestinal tract [14].

Associations of Muc2 with chemical compounds

• To independently identify murine Muc2, we cloned a cDNA fragment from murine colonic mRNA, encoding the 302 NH2-terminal amino acids of murine Muc2 [14].
• Prior to MTX-injection, tumor necrosis factor-alpha and interleukin-10 mRNAs were upregulated in Muc2(-/-) mice, probably due to continuous exposure of the intestine to luminal antigens [4].
• The mucin Muc2, which is a major determinant of goblet cell morphology, was expressed in most goblet cells, yet only in cells staining positive for both Alcian blue and high iron diamine [15].
• Muc2 in distal IL10-/- colon contained significantly less sulfate residues than in controls, which may compromise its protective properties [15].
• MCM levels were decreased 4-fold at 7 days of allergen exposure in -/- mice and at 15 days in +/+ mice [16].

Physical interactions of Muc2

• Two discrete types of mucin proteins exist in the mouse intestine, secretory Muc2 and membrane-bound Muc3 [17].

Regulatory relationships of Muc2

• Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2-/- mice [1].

Other interactions of Muc2

• Therefore, we mated p21(-/-) mice with mice carrying a genetic deficiency of the Muc2 gene, which encodes the major gastrointestinal mucin [1].
• Little or no Muc2 and Muc5b mRNAs were detected [18].
• Increased Muc5ac and Muc2 mRNA expression occurred following ovalbumin or IL13, but not saline, exposure [19].
• To determine whether changes in steady-state mucin gene expression (Muc2 and Muc5ac) are associated with inflammatory cell accumulation and neutrophil elastase activity, FVB/N mice were exposed to acrolein (3.0 parts/million; 6 h/day, 5 days/wk for 3 wk) [20].
• Northern blots were examined for somatostatin, intestinal trefoil factor and mucin-2 [21].

Analytical, diagnostic and therapeutic context of Muc2

• Muc2 and Muc3 gene expression were measured by quantitative reverse-transcriptase polymerase chain reaction [11].
• Furthermore, by a combination of gel shift analysis and site-directed mutagenesis, we have identified the relative contribution of individual GC boxes, and of the factors they bind, to the regulation of the mouse Muc2 promoter, which appears to be different in the mouse and human genes [22].
• In situ hybridization showed that the murine Muc2 mRNA was confined to intestinal goblet cells [14].
• Northern blotting with a murine Muc2 cDNA probe showed hybridization to a very large mRNA, which was expressed highly in the colon and to some extend in the small intestine but was absent in the stomach [14].
• Western blotting, immunoprecipitation of metabolically labeled mucins, and immunohistochemistry showed that murine Muc2 was expressed in the colon and the small intestine but was absent in the stomach [14].

References