The gastrointestinal mucus system in health and disease

Nature Reviews Gastroenterology and Hepatology

Volumn 10, Issue 6, 2013, Pages 352-361

  Johansson, Malin E V ^a   Sjövall, Henrik ^b   Hansson, Gunnar C ^a  

^a UNIVERSITY OF GOTHENBURG   (Sweden)

^b SAHLGRENSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROCHLORIC ACID; MUCIN; MUCIN 1; MUCIN 12; MUCIN 13; MUCIN 16; MUCIN 17; MUCIN 2; MUCIN 3; MUCIN 4; MUCIN 5AC; MUCIN 5B; MUCIN 6; MUCIN 7; UNCLASSIFIED DRUG;

COLON; COLON ISCHEMIA; COMMENSAL; CYSTIC FIBROSIS; EPITHELIUM; EXOCYTOSIS; GASTROINTESTINAL DISEASE; GASTROINTESTINAL TRACT; GOBLET CELL; HUMAN; IMMUNE SYSTEM; INFLAMMATION; INTESTINE CELL; MUCUS; NONHUMAN; PATHOGENICITY; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTECTION; REVIEW; SMALL INTESTINE; STOMACH; ULCERATIVE COLITIS;

COLITIS; COLON; GASTROINTESTINAL DISEASES; GASTROINTESTINAL TRACT; HUMANS; INTESTINE, SMALL; MUCUS; STOMACH;

EID: 84878926402     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2013.35     Document Type: Review

References (158)

1. Kim, Y. S. & Ho, S. B. Intestinal goblet cells and mucins in health and disease: Recent insights and progress. Curr. Gastroenterol. Rep. 12, 319-330 (2010
2. Neutra, M. R., O'Malley, L. J. & Specian, R. D. Regulation of intestinal goblet cell secretion. II. A survey of potentid secretugogues. Am. J. Physiol. Gastroint. Liver Physiol. 242, G380-G387 (1982).
3. Ito, S. Structure and function of the glycocalyx. Fed. Proc. 28, 12-25 (1969
4. Soergel, K. H. & Ingelfinger, F. J Composition of rectal mucus in normal subjects and patients with ulcerative colitis. Gastroenterology 47, 610-616 (1964
5. Rhodes, J M. Colonic mucus and mucosal glycoproteins: The key to colitis and cancer? Gut 30, 1660-1666 (1989
6. Hollingsworth, M. A. & Swanson, B. J. Mucin in cancer: Protection and control of the cell surface. Nat. Rev. Cancer 4, 45-60 (2004
7. Hattrup, C. L. & Gendler, S. J. Structure and function of the cell surface (tethered) mucins. Ann. Rev. Physiol. 70, 431-457 (2008
8. Thornton, D. J., Rousseau, K. & McGuckin, M. A. Structure and function of the polymeric mucins in airways mucus. Ann. Rev. Physiol. 70, 459-486 (2008
9. McGuckin, M. A., Linden, S. K., Sutton, P. & Florin, T. H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265-278 (2011
10. Johansson, M. E. V. et al. Composition and functional role of the mucus layers in the intestine. Cell Mol. Life Sci. 68, 3535-3641 (2011
11. Lang, T., Hansson, G. C. & Samuelsson, T. Gel-forming mucins appeared early in metazoan evolution. Proc. Natl Acad. Sci. USA 104, 16209-16214 (2007
12. Fowler, J., Vinall, L. & Swallow, D. Polymorphism of the human MUC genes. Front. Biosci. 6, D1207-D1215 (2001
13. Gum, J. R., Hicks, J. W., Toribara, N. W., Siddiki, B. & Kim, Y. S. Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. J. Biol. Chem. 269, 2440-2446 (1994
14. Bennett, E. P. et al. Control of mucin-Type O glycosylation: A classification of the polypeptide GalNAc-Transferase gene family. Glycobiology 22, 736-756 (2012
15. Jensen, P. H., Kolarich, D. & Packer, N. H. Mucin-Type O glycosylation-putting the pieces together. FEBS J. 277, 81-94 (2010
16. Larsson, J. M., Karlsson, H., Sjovall, H. & Hansson, G. C. A complex, but uniform O glycosylation of the human MUC2 mucin from colonic biopsies analyzed by nanoLC/MSn. Glycobiology 19, 756-766 (2009).
17. Ambort, D. et al. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc. Natl Acad. Sci. USA 109, 5645-5650 (2012
18. Ligtenberg, M. J. L. et al. Cell-Associated episialin is a complex containing two proteins derived from a common precursor. J. Biol. Chem. 267, 6171-6177 (1992
19. Palmai-Pallag, T. et al. The role of the SEA (sea urchin sperm protein, enterokinase and agrin) module in cleavage of membrane-Tethered mucins. FEBS J. 272, 2901-2911 (2005
20. Levitin, F. et al. The MUC1 SEA module is a self cleaving domain. J. Biol. Chem. 280, 33374-33386 (2005
21. Macao, B., Johansson, D. G. A., Hansson, G. C. & Härd, T. Auto-proteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin. Nat. Struct. Mol. Biol. 13, 71-76 (2006
22. Pelaseyed, T. et al. Unfolding dynamics of the mucin SEA domain probed by force spectroscopy suggest that it acts as a cell protective device. FEBS J. http://dx.doi.org/10.1111/febs.12144
23. Soto, P., Zhang, J. & Carraway, K. L. Enzymatic cleavage as a processing step in the maturation of Muc4/sialomucin complex. J. Cell. Biochem. 97, 1267-1274 (2006
24. Lidell, M. E. & Hansson, G. C. Cleavage in the GDPH sequence of the C terminal cysteine-rich part of the human MUC5AC mucin. Biochem. J. 399, 121-129 (2006
25. Weiss, A. A., Babyatsky, M. W., Ogata, S., Chen, A. & Itzkowitz, S. H. Expression of MUC2 and MUC3 mRNA in human normal, malignant, and inflammatory intestinal tissues. J. Histochem. Cytochem. 44, 1161-1166 (1996
26. Williams, S. J. et al. Two novel mucin genes down-regulated in colorectal cancer identified by differential display. Cancer Res. 59, 4083-4089 (1999
27. Williams, S. J. et al. MUC13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J. Biol. Chem. 276, 18327-18336 (2001
28. Button, B. et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 337, 937-941 (2012
29. Linden, S. K. et al. MUC1 limits helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy. PLoS Pathog. 5, e1000617 (2009
30. Gendler, S. Muc1, The renaissance molecule. J. Mammary Gland Biol. Neoplasia 6, 339-353 (2001
31. Yamamoto, M., Bharti, A., Li, Y. & Kufe, D. Interaction of the DF3/MUC1 breast carcinoma-Associated antigen and beta catenin in cell adhesion. J. Biol. Chem. 272, 12492-12494 (1997
32. Wen, Y. F., Caffrey, T. C., Wheelock, M. J., Johnson, K. R. & Hollingsworth, M. A. Nuclear association of the cytoplasmic tail of MUC1 and beta-catenin. J. Biol. Chem. 278, 38029-38039 (2003
33. Schroeder, J. C. et al. MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene 23, 5739-5747 (2004
34. Malmberg, E. K. et al. The transmembrane MUC17 mucin C terminus binds to the scaffold protein PDZK1 that stably localizes it to the enterocyte apical membrane in the small intestine. Biochem. J. 410, 283-289 (2008
35. LaLonde, D. P., Garbett, D. & Bretscher, A. A. Regulated complex of the scaffolding proteins PDZK1 and EBP50 with ezrin contribute to microvillar organization. Mol. Biol. Cell 21, 1519-1529 (2010
36. Donowitz, M. & Li, X. Regulatory binding partners and complexes of NHE3. Physiol. Rev. 87, 825-872 (2007
37. Singh, P. K. & Hollingsworth, M. A. Cell surface-Associated mucins in signal transduction. Trends Cell Biol. 16, 467-476 (2006
38. Caldara, M. et al. Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state. Curr. Biol. 22, 2325-2330 (2012
39. Atuma, C., Strugula, V., Allen, A. & Holm, L. The adherent gastrointestinal mucus gel layer: Thickness and physical state in vivo. Am. J. Physiol. 280, G922-G929 (2001
40. Khan, S. H., Aguirre, A. & Bobek, L. A. In-situ hybridization localized MUC7 mucin gene expression to the mucous acinar cells of human and MUC7-Transgenic mouse salivary glands. Glycoconj. J. 15, 1125-1132 (1998
41. Bobek, L. A., Tsai, H., Biesbrock, A. R. & Levine, M. J. Molecular cloning, sequence, and specificity of expression of the gene encoding the low molecular weight human salivary mucin (MUC7). J. Biol. Chem. 268, 20563-20569 (1993
42. Nielsen, P. A., Mandel, U., Therkildsen, M. H. & Clausen, H. Differential expression of human high molecular weight salivary mucin (MG1) and low molecular weight salivary mucin (MG2). J. Dental Res. 75, 1820-1826 (1996
43. Thornton, D. J. et al. Salivary mucin MG1 is comprised almost entirely of different glycosylated forms of the MUC5B gene product. Glycobiology 9, 293-302 (1999
44. Wickstrom, C., Davies, J. R., Eriksen, G. V., Veerman, E. C. I. & Carlstedt, I. MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: Identification of glycoforms and C terminal cleavage. Biochem. J. 334, 685-693 (1998
45. Ho, S. B. et al. Expression cloning of gastric mucin complementary DNA and localization of mucin gene expression. Gastroenterology 109, 735-747 (1995
46. Nordman, H. et al. Gastric MUC5AC and MUC6 are large oligomeric mucins that differ in size, glycosylation and tissue distribution. Biochem. J. 364, 191-200 (2002
47. Debolos, C., Garrido, M. & Real, F. X. MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach. Gastroenterology 109, 723-734 (1995
48. Bartman, A. E. et al. The MUC6 secretory mucin genets expressed in a wide variety of epithelial tissues. J. Pathol. 186, 398-405 (1998
49. Audie, J. P. et al. Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J. Histochem. Cytochem. 41, 1479-1485 (1993
50. Johansson, M. E. V. et al. The inner of the two Muc2 mucin dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064-15069 (2008
51. Godl, K. et al. The N termini of the MUC2 mucin form trimers that are held together within a trypsin-resistant core fragment. J. Biol. Chem. 277, 47248-47256 (2002
52. Lidell, M. E. et al. The recombinant C terminus of the human MUC2 mucin forms dimers in CHO cells and heterodimers with full-length MUC2 in LS 174T cells. Biochem. J. 372, 335-345 (2003
53. Round, A. N. et al. Lamellar structures of MUC2-rich mucin: A potential role in governing the barrier and lubricating functions of intestinal mucus. Biomacromolecules 13, 3253-3261 (2012
54. Johansson, M. E. V. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS ONE 7, e41009 (2012
55. Schade, C., Flemstrom, G. & Holm, L. Hydrogen ion concentration in the mucus layer on top of acid-stimulated and -inhibited rat gastric mucosa. Gastroenterology 107, 180-188 (1994
56. Phillipson, M., Atuma, C., Henriksnas, J. & Holm, L. The importance of mucus layers and bicarbonate transport in preservation of gastric juxtamucosal pH. Am. J. Physiol. 282, G211-G219 (2002
57. Allen, A. & Flemstrom, G. Gastroduodenal mucus bicarbonate barrier: Protection against acid and pepsin. Am. J. Physiol. Cell Physiol. 288, C1-C19 (2005
58. Bhaskar, K. R. et al. Viscous fingering of HCl through gastric mucin. Nature 360, 458-461 (1992
59. Johansson, M., Synnerstad, I. & Holm, L. Acid transport through channels in the mucous layer of rat stomach. Gastroenterology 119, 1297-1304 (2000
60. Ho, S. B. et al. The adherent gastric mucous layer is composed of alternating layers of MUC5AC and MUC6 mucin proteins. Dig. Dis. Sci. 49, 1598-1606 (2004
61. Phillipson, M. et al. The gastric mucus layers: Constituents and regulation of accumulation. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G806-G812 (2008
62. Baxter, P. S. et al. Abnormal jejunal potential difference in cystic fibrosis. Lancet 333, 464-466 (1989
63. Deloose, E., Janssen, P., Depoortere, I. & Tack, J. The migrating motor complex: Control mechanisms and its role in health and disease. Nat. Rev. Gastroenterol. Hepatol. 9, 271-285 (2012
64. Ouellette, A. J. Paneth cells and innate mucosal immunity. Curr. Opin. Gastroenterol. 26, 547-553 (2010
65. Vaishnava, S. et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255-258 (2011
66. Chu, H. et al. Human defensin 6 promotes mucosal innate immunity through self-Assembled peptide nanonets. Science 337, 477-481 (2012
67. Johansson, M. E. V. & Hansson, G. C. Keeping bacteria at a distance. Science 334, 182-183 (2011
68. Rosenstiel, P. et al. Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion. J. Immunol. 178, 8203-8211 (2007
69. Riordan, J. R. CFTR function and prospects for therapy. Annu. Rev. Biochem. 77, 701-726 (2008
70. O'Sullivan, B. P. & Freedman, S. D. Cystic fibrosis. Lancet 373, 1891-1904 (2009
71. Houwen, R. H. et al. Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS. J. Pediatr. Gastroenterol. Nutr. 50, 38-42 (2010
72. Grubb, B. R. & Gabriel, S. E. Intestinal physiology and pathology in gene-Targeted mouse models of cystic fibrosis. Am. J. Physiol. 273, G258-G266 (1997
73. French, P. J. et al. A Delta F508 mutation in mouse cystic fibrosis transmembrane conductance regulator results in a temperature-sensitive processing defect in vivo. J. Clin. Invest. 98, 1304-1312 (1996
74. Rogers, C. S. et al. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321, 1837-1841 (2008
75. Gustafsson, J. K. et al. Bicarbonate and functional CFTR channel is required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J. Exp. Med. 209, 1263-1272 (2012
76. De Lisle, R. C., Roach, E. & Jansson, K. Effects of laxative and N acetylcysteine on mucus accumulation, bacterial load, transit, and inflammation in the cystic fibrosis mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G577-G584 (2007
77. Fridge, J. L., Conrad, C., Gerson, L., Castillo, R. O. & Cox, K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J. Pediatr. Gastroenterol. Nutr. 44, 212-218 (2007
78. Malmberg, E. K. et al. Increased levels of mucins in the cystic fibrosis mouse small intestine and modulator effects of the Muc1 mucin expression. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G203-G210 (2006
79. Delisle, R. C., Roach, E. A. & Norkina, O. Eradicaion of small intestinal bacterial overgrowth in the cystic fibrosis mouse reduces mucus accumulation. J. Pediatr. Gastroenterol. Nutr. 42, 46-52 (2006
80. Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915-1920 (2005
81. Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-Adapted bacterial symbiont. Science 307, 1955-1959 (2005
82. Wong, J. M., de Souza, R., Kendall, C. W., Emam, A. & Jenkins, D. J. Colonic health: Fermentation and short chain fatty acids. J. Clin. Gastroenterol. 40, 235-243 (2006
83. Rawls, J. F., Mahowald, M. A., Ley, R. E. & Gordon, J. I. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127, 423-433 (2006
84. Bergstrom, K. S. B. et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. 6, e1000902 (2010
85. Moore, M. E., Boren, T. & Solnick, J. V. Life at the margins: Modulation of attachment proteins in Helicobacter pylori. Gut Microbes 2, 42-46 (2011
86. Else, K. J. & Finkelman, F. D. Intestinal nematode parasites, cytokines and effector mechanisms. Int. J. Parasitol. 28, 1145-1158 (1998
87. Ishikawa, N., Horii, Y. & Nawa, Y. Immune-mediated alteration of the terminal sugars of goblet cell mucins in the small intestine of Nippostrongylus brasiliensis-infected rats. Immunology 78, 303-307 (1993
88. Ishikawa, N., Wakelin, D. & Mahida, Y. R. Role of T helper 2 cells in intestinal goblet cell hyperplasia in mice infected with Trichinella spiralis. Gastroenterology 113, 542-549 (1997
89. Koninkx, J. F., Mirck, M. H., Hendriks, H. G., Mouwen, J. M. & van Dijk, J. E. Nippostrongylus brasiliensis: Histochemical changes in the composition of mucins in goblet cells during infection in rats. Exp. Parasitol. 65, 84-90 (1988
90. McKay, D. M. et al. Hymenolepis diminuta: Intestinal goblet cell response to infection in male C57 mice. Exp. Parasitol. 71, 9-20 (1990
91. Hasnain, S. Z. et al. Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Gastroenterology 138, 1763-1771 (2010
92. Hasnain, S. Z. et al. Muc5ac: A critical component mediating the rejection of enteric nematodes. J Exp. Med. 208, 893-900 (2011
93. Finkelman, F. D. et al. Interleukin 4 and interleukin 13 mediated host protection against intestinal nematode parasites. Immunol. Rev. 201, 139-155 (2004
94. Biton, M. et al. Epithelial microRNAs regulate gut mucosal immunity via epithelium T cell crosstalk. Nat. Immunol. 12, 239-246 (2011
95. Petri, W. A., Haque, R. & Mann, B. J. The bittersweet interface of parasite and host: Lectin-carbohydrate interactions during human invasion by the parasite Entamoeba histolytica. Annu. Rev. Microbiol. 56, 39-64 (2002
96. Moncada, D., Keller, K. & Chadee, K. Entamoeba histolytica cysteine proteinases disrupt the polymeric structure of colonic mucin and alter its protective function. Infec. Immun. 71, 838-844 (2003
97. Lidell, M. E., Moncada, D. M., Chadee, K. & Hansson, G. C. Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C terminal part and dissolves the protective colonic mucus gel. Proc. Natl Acad. Sci. USA 103, 9298-9393 (2006
98. Brandt, L. J., Feuerstadt, P. & Blaszka, M. C. Anatomic patterns, patient characteristics, and clinical outcomes in ischemic colitis: A study of 313 cases supported by histology. Am. J. Gastroenterol. 105, 2245-2252 (2010
99. [No authors listed] American Gastroenterological Association Medical Position Statement: Guidelines on intestinal ischemia. Gastroenterology 118, 951-953 (2000
100. Grootjans, J. et al. Ischemia-induced mucus barrier loss and bacterial penetration are rapidly counteracted by increased goblet cell secretory activity in human and rat colon. Gut 62, 259-258 (2013
101. Specian, D. & Neutra, M. R. Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine. J. Cell Biol. 85, 626-640 (1980
102. Plaisancie, P. et al. Effects of neurotransmitters, gut hormones, and inflammatory mediators on mucus discharge in rat colon. Am. J. Physiol. 275, G1073-G1084 (1998
103. Johansson, M. E. V. & Hansson, G. C. The goblet cell: A key player in ischemia-reperfusion injury. Gut 62, 188-189 (2012
104. Ordas, I., Eckmann, L., Talamini, M., Baumgart, D. C. & Sandborn, W. J. Ulcerative colitis. Lancet 380, 1609-1619 (2012
105. Swidsinski, A. et al. Comparative study of the intestinal mucus barrier in normal and inflamed colon. Gut 56, 343-350 (2007
106. Velcich, A, et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726-1729 (2002
107. Van Der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117-129 (2006
108. Heazlewood, C. K. et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 5, e54 (2008
109. Dawson, P. A. et al. Impaired intestinal function in the hyposulphataemic NaS1 null mouse. Gut 58, 910-919 (2009
110. Fu, J. et al. Loss of intestinal core 1 derived O glycans causes spontaneous colitis. J. Clin. Invest. 121, 1657-1666 (2011
111. Johansson, M. E. V. et al. Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. PLoS ONE 5, e12238 (2010).
112. Johansson, M. E. V. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and in patients with ulcerative colitis. Gut http://dx.doi.org/10.1136/gutjnl-2012-303207
113. Gustafsson, J. K., Hansson, G. C. & Sjovall, H. Ulcerative colitis patients in remission have an altered secretory capacity in the proximal colon despite macroscopically normal mucosa. Neurogastroenterol. Motil. 24, e381-e391 (2012
114. Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743-756 (2008
115. Eri, R. D. et al. An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity. Mucosal Immunol. 4, 354-364 (2011
116. Park, S. W. et al. The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc. Natl Acad. Sci. USA 106, 6950-6955 (2009
117. Zhao, F. et al. Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2 /-mice. Develop. Biol. 338, 270-279 (2010
118. Lan, M. S., Batra, S. K., Qi, W., Metzgar, R. S. & Hollingsworth, M. A. Cloning and sequencing of a human pancreatic tumor mucin cDNA. J. Biol. Chem. 265, 15294-15299 (1990
119. Ligtenberg, M. J. L., Vos, H. L., Gennissen, A. M. C. & Hilkens, J. Episialin, a carcinoma-Associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini. J. Biol. Chem. 265, 5573-5578 (1990
120. Gendler, S. J. et al. Molecular cloning and expression of human tumor-Associated polymorphic epithelial mucin. J. Biol. Chem. 265, 15286-15293 (1990
121. Lancaster, C. A. et al. Structure and expression of the human polymorphic epithelial mucin gene: An expressed VNTR unit. Biochem. Biophys. Res. Commun. 173, 1019-1029 (1990
122. Wreschner, D. H. et al. Human epithelial tumor antigen cDNA sequences. Differential splicing may generate multiple protein forms. Eur. J. Biochem. 189, 463-473 (1990
123. McAuley, J. L. et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J. Clin. Invest. 117, 2313-2324 (2007
124. Linden, S. K., Florin, T. H. & McGuckin, M. A. Mucin dynamics in intestinal bacterial infection. PLoS ONE 3, e3952 (2008
125. Gum, J. R. et al. Molecular cloning of human intestinal mucin cDNAs sequence analysis and evidence for genetic polymorphism. J. Biol. Chem. 264, 6480-6487 (1989
126. Gum, J. R. et al. The human MUC2 intestinal mucin has cysteine-rich subdomains located both upstream and downstream of its central repetitive region. J. Biol. Chem. 267, 21375-21383 (1992
127. Gum, J. R. et al. Molecular cloning of cDNAs derived from a novel human intestinal mucin gene. Biochem. Biophys. Res. Commun. 171, 407-415 (1990
128. Gum, J. R. et al. MUC3 human intestinal mucin. J. Biol. Chem. 272, 26678-26686 (1997
129. Crawley, S. C. et al. Genomic organization and structure of the 3' region of human MUC3: Alternative splicing predicts membrane-bound and soluble forms of the mucin. Biochem. Biophys. Res. Commun. 263, 728-736 (1999
130. Moniaux, N., Nollet, S., Degand, P., Laine, A. & Aubert, J. P. Complete sequence of the human mucin MUC4: A putative cell membrane-Associated mucin. Biochem. J. 338, 325-333 (1999
131. Escande, F. et al. Genomic organization of MUC4 mucin gene. Towards the characterization of splice variants. Eur. J. Biochem. 269, 3637-3644 (2002
132. Price-Schiavi, S. A., Perez, A., Barco, R. & Carraway, K. L. Cloning and characterization of the 5' flanking region of the sialomucin complex/rat Muc4 gene: Promoter activity in cultured cells. Biochem. J. 349, 641-649 (2000
133. Rong, M. et al. Expression and localization of Muc4/sialomucin complex (SMC) in the adult and developing rat intestine: Implications for Muc4/SMC function. J. Cell. Physiol 202, 275-284 (2005
134. Buisine, M. P. et al. Genomic organization of the 3'-region of the human MUC5AC mucin gene: Additional evidence for a common ancestral gene for the 11p15.5 mucin gene family. Biochem. J. 332, 729-738 (1998
135. Escande, F., Aubert, J. P., Porchet, N. & Buisine, M. P. Human mucin gene MUC5AC: Organization of its 5'-region and central repetitive region. Biochem. J. 358, 763-772 (2001
136. Li, D. Z., Gallup, M., Fan, N., Szymkowski, D. E. & Basbaum, C. B. Cloning of the amino-Terminal and 5'-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. J. Biol. Chem. 273, 6812-6820 (1998
137. Klomp, L. W. J., Vanrens, L. & Strous, G. J. Cloning and analysis of human gastric mucin cDNA reveals two types of conserved cysteine-rich domains. Biochem. J. 308, 831-838 (1995
138. Meerzaman, D. et al. Cloning and analysis of cDNA encoding a major airway glycoprotein, human tracheobronchial mucin (Muc5). J. Biol. Chem. 269, 12932-12939 (1994
139. Keates, A. C., Nunes, D. P., Afdhal, N. H., Troxler, R. F. & Offner, G. D. Molecular cloning of a major human gall bladder mucin: Complete C terminal sequence and genomic organization of MUC5B. Biochem. J. 324, 295-303 (1997
140. Offner, G. D., Nunes, D. P., Keates, A. C., Afdhal, N. H. & Troxler, R. F. The amino-Terminal sequence of MUC5B contains conserved multifunctional D domains: Implications for tissue-specific mucin functions. Biochem. Biophys. Res. Commun. 251, 350-355 (1998
141. Troxler, R. F., Offner, G. D., Zhang, F., Iontcheva, I. & Oppenheim, F. G. Molecular cloning of a novel high molecular weight mucin (MG1) from human sublingual gland. Biochem. Biophys. Res. Commun. 217, 1112-1119 (1995
142. Toribara, N. W. et al. Human gastric mucin. J. Biol. Chem. 268, 5879-5885 (1993
143. Toribara, N. W. et al. The carboxyl-Terminal sequence of the human secretory mucin, MUC6. J. Biol. Chem. 272, 16398-16403 (1997
144. Rousseau, K. et al. The complete genomic organization of the human MUC6 and MUC2 mucin genes. Genomics 83, 936-939 (2004
145. Situ, H., Wei, G., Smith, C. J., Mashhoon, S. & Bobek, L. A. Human salivary MUC7 mucin peptides: Effect of size, charge and cysteine residues on antifungal activity. Biochem. J. 375, 175-182 (2003
146. Sheng, Y. H. et al. The MUC13 cell-surface mucin protects against intestinal inflammation by inhibiting epithelial cell apoptosis. Gut 60, 1661-1670 (2011
147. Yin, B. W. T. & Lloyd, K. Molecular cloning of the CA125 ovarian cancer antigen. J. Biol. Chem. 276, 27371-27375 (2001
148. O'Brien, T. J., Beard, J. B., Underwood, L. J. & Shigemasa, K. The CA125 gene: A newly discovered extesion of the glycosylated N terminal domain doubles the size of this extracellular superstructure. Tumor Biol. 23, 154-169 (2004
149. Gum, J. R., Crawley, S. C., Hicks, J. W., Szymkowski, D. E. & Kim, Y. S. MUC17, a novel membrane-Tethered mucin. Biochem. Biophys. Res. Commun. 291, 466-475 (2002
150. Pratt, W. S. et al. Multiple transcripts of MUC3: Evidence for two genes MUC3A and MUC3B. Biochem. Biophys. Res. Commun. 275, 916-923 (2000
151. Pullan, R. D. et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut 35, 353-359 (1994
152. Debailleul, V. et al. Human mucin genes MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC6 express stable and extremely large mRNAs and exhibit a variable length polymorphism. J. Biol. Chem. 273, 881-890 (1998
153. Ogata, S., Uehara, H., Chen, A. & Itzkowitz, S. H. Mucin gene expression in colonic tissues and cell lines. Cancer Res. 52, 5971-5978 (1992
154. Vanklinken, B. J. W. et al. MUC5B is the prominent mucin in human gallbladder and is also expressed in a subset of colonic goblet cells. Am. J. Physiol. 37, G871-G878 (1998
155. Peat, N., Gendler, S. J., Lalani, N., Duhig, T. & Taylor-Papadimitriou, J. Tissue-specific expression of a human polymorphic epithelial mucin (MUC1) in transgenic mice. Cancer Res. 52, 1954-1960 (1992
156. Zhang, J., Yasin, M., Carraway, C. A. & Carraway, K. L. MUC4 expression and localization in gastrointestinal tract and skin of human embryos. Tissue Cell 38, 271-275 (2006
157. Gonzalez-Begne, M. et al. Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). J. Proteome Res. 8, 1304-1314 (2009
158. Senapati, S. et al. Expression of intestinal MUC17 membrane-bound mucin in inflammatory and neoplastic diseases of the colon. J. Clin. Pathol. 63, 702-707 (2010