MUC2 gene is the first human secretory mucin gene to be cloned and fully sequenced (Gum et al., 1994).

MUC2 is located within a 29-kb DNA fragment between MUC6, MUC5AC and MUCB on chromosome 11 in the region p15.5 (Griffiths et al., 1990; Desseyn et al., 1998; Rousseau et al., 2004), and cDNA is approximately 15.5 kb long. Genes that share some sequence homology are believed to have arisen by duplication from a common ancestor.

The MUC2 promoter contains a TATA box, and includes binding sequence motifs for transcription factors such as AP2, SP1 and CDX2 (Griffiths et al., 1990; Toribara et al., 1991; Gum et al., 1994). MUC2 expression has been reported to be regulated by the Sp family (Nogami et al., 1997; Aslam et al., 2001). SP1 activates transcription synergistically both close to and far from the transcription start site in an enhancer-like manner. In several human cancer cell lines, p53 has also been indicated to regulate MUC2 transactivation by binding to two of its sites (-1131/-1100 and -676/-650) (Ookawa et al., 2002). Moreover, NF-kB and CDX2 have been reported to up-regulate MUC2 transcription (Yamamoto et al., 2003; Ikeda et al., 2007). Methylation of cytosine residues at CpG dinucleotides is an important epigenetic change that has been linked to transcriptional repression and regulation of chromatin structure (Holliday et al., 1975; Meehan et al., 2001; Recillas-Targa et al., 2002). Increased methylation of promoter region causes suppression of MUC2 gene (Hanski et al., 1997b; Riede et al., 1998). Hamada et al. have determined the detailed methylation status of a wide area of the MUC2 promoter region in pancreatic cancer cell lines, and suggested that methylation of certain CpG sites may play a particularly important role in the regulation of MUC2 transcription (Hamada et al., 2005). A CDX2 binding site is present downstream of the MUC2 promoter, and Yamamoto et al. have reported that the homeodomain protein CDX2 interacts with the MUC2-WT cis element (bases -201 to -162) in the MUC2 promoter and that ectopic expression of the CDX2 protein activates transcription of MUC2 (Yamamoto et al., 2003). In bisulfite genomic sequencing study, CDX2-binding CpG site showed 95% methylation in PANC1 (MUC2-negative) and 50% methylation in BxPC3 (MUC2-positive) (Hamada et al., 2005). Thus, MUC2 expression might be regulated by epigenetic changes in the promoter region containing the CDX2 binding site. In addition to DNA methylation, H3-K9 methylation is closely related to DNA methylation and acts as an epigenetic marker for silencing of the MUC2 gene (Yamada et al., 2006; Vincent et al., 2007).

MUC2 is one of the human gel-forming secreted mucins, and has a unique core peptide composed of 23 amino acids. The N-terminal and C-terminal regions of the MUC2 apomucin are very similar to von Willebrand factor (vWF). The N-terminal region is composed of disulfide-rich D-domains (D1, D2, D and D3) which is seen in vWF. The C-terminal region has also domains seen in vWF (D4, B, C and CK). In the central part, there are the first Ser/Thr/Pro rich 21 repetitive region showing an irregular amino acid motif, and the second regular tandemly repeated motifs of 23 amino acids (PTTTPITTTTTVTPTPTPTGTQT) which show variable number of tandem repeat from 51 to 115. CYS domain are present between the N-terminal region and the first Ser/Thr/Pro rich 21 repetitive region, and also present between the first Ser/Thr/Pro rich repetitive region and the second 23 amino acids repetitive region.

The central repetitive domains are rigid owing to heavy glycosylation, whereas the unique sequences of N-terminal and C-terminal regions sparsely glycosylated and protease-sensitive. In addition, the unique sequences have numerous Cys residues that link monomers to oligomers by disulfide bonds.

In normal physiological situation, MUC2 shows unique expression profiles in the limited organs and tissues such as intestine, bronchus and salivary gland.
In the normal human adult intestinal system, MUC2 expression is observed in the perinuclear areas of the goblet cells in the villi and crypts of the small intestine, and in the crypts of the colon and rectum, but not in the surface absorptive cells. MUC2 mRNA expression is also demonstrated at the perinuclear areas of those goblet cells (Chang et al., 1994; Buisine et al., 1998). Precise in situ hybridization (ISH) and immunohistochemistry (IHC) studies in electron microscopic level study demonstrated that MUC2 mRNA and MUC2 apomucin are located predominantly in the supranuclear and the perinuclear rough endoplasmic reticulum (RER), but not in the Golgi apparatus, in the goblet cells (Wang et al., 2001).
In ISH study in human embryonic and fetal tissues, in small intestine, MUC2 mRNA was detected between the primordial villi at 9 weeks after gestation, and was located mainly in immature crypts of Lieberkuhn after 10 weeks until 23 weeks. After that, MUC2 mRNA was expressed at the perinuclear regions of the goblet cells in villi and crypts. In the colon and rectum, MUC2 mRNA was detected at the perinulear regions of the goblet cells in crypts from 13 weeks of gestation (Buisine et al., 1998).
In the bronchial tissue, MUC2 was expressed below and around mucous secretory granules (RER and Golgi apparatus) in the bronchial surface epithelium and bronchial mucous glands (Jany et al., 1991).
Second-generation MAb to MUC2 (CCP58) detects weak expression in salivary glands in addition to the intense expression in the small and large intestine as described above glands (Xing et al., 1992).

After the multimerization forming oligomers and O-glycosylation, MUC2 mucin is stored in secretory granules. MUC2 is localized in the supra- and peri-nuclear areas, which are RER (Wang et al., 2001), of the columnar epithelium with goblets in small and large intestine. MUC2 is also seen in the peribronchial glands.

MUC2 mucin form gel layer which covers the intestinal mucosa, protect the mucosal surface, and plays a role of lubricant particularly at the large intestine. MUC2 also has a function as a tumor suppressor. MUC2 knockout mice frequently develop tumors in the small intestine, colon and rectum where MUC2 is predominantly expressed in the normal condition (Velcich et al., 2002). Alteration in protection and lubrication of the intestinal mucosal surface by the lack of MUC2 might induce an increase of bacterial flora carrying pro-carcinogenic effect, or might result in release of intestinal mucosa-derived factors which are normally depressed by MUC2 stimulating pro-carcinogenic factors, or might lead to destruction of a physical barrier of MUC2 to dietary carcinogens. Loss of MUC2 might compromise the signaling which contributes to the epithelial differentiation and proliferation through the contacts with membrane-bound mucins, or might alterate in the differentiation program of the intestinal mucosa resulting in the increased probability of tumor formation. High levels of MUC2 expression in indolent human pancreatobiliary neoplasms with a favorable prognosis (Osako et al., 1993; Yamashita et al., 1993; Yonezawa et al., 1997b; Yonezawa et al., 1997a; Yonezawa et al., 2008a) might be related with tumor suppressor activity by MUC2.

The human gel-forming mucins, MUC5AC, MUC5B and MUC6, whose genes are located on chromosome 11p15.5 like MUC2, show homology with MUC2. MUC19, whose gene is located on chromosome 12q12, also has homology with MUC2. N-terminal and C-terminal regions of MUC5AC and MUC5B are same as those of MUC2, and are highly similar to those of vWF, in their D, B, C and CK domains which are observed in vWF. N-terminal regions of MUC6 and MUC19 are also same as that of MUC2, but the C-terminal region of MUC6 has only CK domain, and that of MUC19 has C and CK domains.