The MUC2 gene product: a human intestinal mucin

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Abstract

The MUC2 gene product is the first human secretory mucin protein core to be fully sequenced. Like the other eight human MUC genes identified to date, MUC2 is characterised by tandem and irregular repeat sequences rich in threonine and serine, the potential sites of attachment of the oligosaccharide chains. The MUC2 gene product is more than 5100 amino acids in its commonest allelic form and accounts for one fifth by weight of the mucin glycoprotein molecule (80% oligosaccharide side chains). The MUC2 product is polymerised end to end through disulphide bridges to form large secreted polymeric gel-forming mucins (Mr∼107). The primary function of the MUC2 gene product is to provide a protective barrier between the epithelial surfaces and the gut lumen. There is decreased expression of MUC2 in colonic cancer and defective polymerisation of secreted mucin in ulcerative colitis. Elucidation of the MUC2 and other mucin gene sequences has opened the way for a full structural characterisation and an improved understanding of the structure and function of these complex mucus gel secretions.

Introduction

MUC2 is the first human secretory mucin gene to be cloned and completely sequenced1, 2, 3. It is strongly expressed by goblet cells of the human colon and small intestine coding for the protein core (>5100 aa) of a major mucin secretion. Secretory mucins form a protective mucus gel barrier between the epithelia and the damaging environment of the lumen of the gastro-intestinal tract4, 5.

Section snippets

Structure

Mucin (MUC) gene proteins are characterised by tandem repeat sequences rich in threonine and serine, the sites of attachment of the oligosaccharide chains1, 2, 3, 6, 7. To date nine human epithelial mucin genes, identified by their unique tandem repeats, have been cloned. Four of these are expressed in mucus-secreting cells at the same chromosome locus, 11p15.5, in the sequence MUC6, 2, 5AC and 5B[8]. Three MUC genes are fully sequenced, MUC1 (chromosome 1q21), a membrane bound mucin, MUC7

Biosynthesis and degradation

The biosynthesis of MUC2 mucin has been studied in human colonic (premalignant or cancer) epithelial cell lines and rat colonic mucosal explants7, 10, 11. Pulse chase experiments show the first stage is the formation of an N-glycosylated apoprotein, O-glycosylated with just galNAc. Subsequently, a larger protein identified as a dimer of the original apoprotein is identified, analogous to dimerisation in vWF biosynthesis. Complete glycosylation of the dimer occurs in the golgi. The

Biological function

The primary biological function assigned to secretory gastrointestinal mucins is that of a protective gel barrier between the underlying epithelium and the lumen, which in the colon in particular, is teeming with a host of microorganisms, hydrolases, toxins, etc.4, 5, 6. Within the matrix of the adherent mucus layer, continuous and a mean of 150 μm thick in human colon, a stable unstirred, aqueous microenvironment is established which is readily permeable to ions and low molecular weight

Role in disease processes

Marked changes in the colonic mucus are seen in ulcerative colitis and colonic cancer 7, 9, 12, 13. In active ulcerative colitis, the mucus gel layer is severely disrupted and discontinuous with a 60–70% reduction in thickness. Luminal damaging factors may play a key role in the pathophysiology of ulcerative colitis and breakdown of the mucus barrier would allow them to access to the epithelium. In particular, a significant four-fold rise in proteolytic activity in the colonic lumen has been

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    Mucin 2 (MUC2) encodes a human secretory mucin protein. Its major function is to protect the epithelial surface and the gut lumen (Allen et al., 1998). MUC2 is expressed in mucinous breast cancer and may prevent tumor invasion (Rakha et al., 2005).

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