Transmembrane and truncated (SEC) isoforms of MUC1 in the human endometrium and Fallopian tube

Reproductive Biology and Endocrinology

John D Aplin³  María Elena Ortíz¹  Daniel H Wreschner⁴  Nechama I Smorodinsky⁴  Carlos Simón²  Marcos Meseguer²  Neil A Hey³ 

[1] Unidad de Reproducción y Desarollo, Pontificia Universidad Católica de Chile, Santiago, Chile;IVI, Valencia, Spain;Medical School and School of Biological Sciences, University of Manchester, UK;Dept. of Cell Research & Immunology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel 69978

关键词: epithelium;    implantation;    Fallopian tube;    endometrium;    mucin;    MUC1;   

Others  :  1157031
DOI  :  10.1186/1477-7827-1-2

 received in 2003-01-21, accepted in 2003-01-30,  发布年份 2003

【 摘 要 】

The cell surface mucin MUC1 is expressed by endometrial epithelial cells with increased abundance in the secretory phase of the menstrual cycle, when it is found both at the apical cell surface and in secretions. This suggests the presence of a maternal cell surface glycoprotein barrier to embryo implantation, arising from the anti-adhesive property of MUC1. In previous work, we demonstrated alternatively spliced MUC1 variant forms in tumour cells. The variant MUC1/SEC lacks the transmembrane and cytoplasmic sequences found in the full-length variant. We now show that MUC1/SEC mRNA is present in endometrial carcinoma cell lines, endometrial tissue and primary cultured endometrial epithelial cells. The protein can be detected using isoform-specific antibodies in uterine flushings, suggesting release from endometrium in vivo. However, on the basis of immunolocalisation studies, MUC1/SEC also remains associated with the apical epithelial surface both in tissue and in cultured cells. Transmembrane MUC1 and MUC1/SEC are both strikingly localised to the apical surface of tubal epithelium. Thus MUC1 may contribute to the anti-adhesive character of the tubal surface, inhibiting ectopic implantation. The mechanism by which this barrier is overcome in endometrium at implantation is the subject of ongoing investigation.

【 授权许可】

   
2003 Hey et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Gendler SJ, Lancaster CA, Taylor-Papadimitriou J, Duhig T, Peat T, Burchell J, Pemberton L, Lalani E, Wilson D: Molecular cloning and expression of human tumour associated polymorphic epithelial mucin. J Biol Chem 1990, 265:15286-15299.
• [2]Ligtenberg MJL, Kruishaar L, Buijs F, van Meijer M, Litvinov SM, Hilkens J: Cell associated epsialin is a complex containing two proteins derived for a common precursor. J Biol Chem 1992, 267:6171-6177.
• [3]Hey NA, Li TC, Devine P, Graham RA, Aplin JD: MUC1 in secretory phase endometrium: expression in precisely dated biopsies and flushings from normal and recurrent miscarriage patients. Hum Reprod 1995, 10:2655-2662.
• [4]Lancaster CA, Peat N, Duhig T, Wilson D, Taylor-Papadimitriou J, Gendler SJ: Structure and expression of the human polymorphic epithelial mucin gene: an expressed VNTR unit. Biochem Biophys Res Commun 1990, 173:1019-1029.
• [5]Tsarfaty I, Hareuveni M, Horev J, Zaretsky J, Weiss M, Jeltsch JM, Garnier JM, Lathe R, Keydar I, Wreschner DH: Isolation and characterization of an expressed hypervariable gene coding for a breast-cancer-associated antigen. Gene 1990, 93:313-318.
• [6]Hey NA, Graham RA, Seif MW, Aplin JD: The polymorphic epithelial mucin MUC1 in human endometrium is regulated with maximal expression in the implantation phase. J Clin Endocrinol Metab 1994, 78:337-342.
• [7]Girling A, Bartkova J, Burchell J, Gendler S, Gillett C, Taylor-Papadimitriou J: A core protein epitope of the polymorphic epithelial mucin detected by the monoclonal antibody SM-3 is selectively exposed in a range of primary carcinomas. Int J Cancer 1989, 43:1072-1076.
• [8]Parry G, Li J, Stubbs J, Bissell MJ, Schmidhauser C, Spicer AP, Gendler SJ: Studies of Muc-1 mucin expression and polarity in the mouse mammary gland demonstrate developmental regulation of Muc-1 glycosylation and establish the hormonal basis for mRNA expression. J Cell Sci 1992, 101:191-199.
• [9]Wreschner DH, Hareuveni M, Tsarfaty I, Smorodinsky N, Horev J, Zaretsky J, Kotkes P, Weiss M, Lathe R, Dion A, Keydar I: Human epithelial tumor antigen cDNA sequences Differential splicing may generate multiple protein forms. Eur J Biochem 1990, 189:463-473.
• [10]Aplin JD, Hey NA, Graham RA: Human endometrial MUC1 carries keratan sulphate: characteristic glycoforms in the luminal epithelium at receptivity. Glycobiology 1998, 8:269-276.
• [11]Hilkens J, Boer M: Monoclonal antibodies against the nonmucin domain of MUC1/episialin. Tumour Biol 1998, 19:67-70.
• [12]Parry S, Silverman HS, McDermott K, Willis A, Hollingsworth MA, Harris A: Identification of MUC1 proteolytic cleavage sites in vivo. Biochem Biophys Res Commun 2001, 283:715-720.
• [13]Boshell M, Lalani E-N, Pemberton L, Burchell J, Gendler S, Taylor-Papadimitriou J: The product of the human MUC1 gene when secreted by mouse cells transfected with the full length cDNA lacks the cytoplasmic tail. Biochem Biophys Res Commun 1992, 185:1-8.
• [14]Julian J, Carson DD: Formation of MUC1 metabolic complex is conserved in tumor-derived and normal epithelial cells. Biochem Biophys Res Commun 2002, 293:1183-1190.
• [15]Obermair A, Schmid BC, Stimpfl M, Fasching B, Preyer O, Leodolter S, Crandon AJ, Zeillinger R: Novel MUC1 splice variants are expressed in cervical carcinoma. Gynecol Oncol 2001, 83:343-347.
• [16]Obermair A, Schmid BC, Packer LM, Leodolter S, Birner P, Ward BG, Crandon AJ, McGuckin MA, Zeillinger R: Expression of MUC1 splice variants in benign and malignant ovarian tumours. Int J Cancer 2002, 100:166-171.
• [17]Li TC, Ling E, Dalton C, Bolton AE, Cooke ID: Concentration of endometrial protein PP14 in uterine flushings throughout the menstrual cycle in normal fertile women. Br J Obstet Gynaecol 1993, 100:460-464.
• [18]Campbell S, Seif MW, Aplin JD, Richmond SJ, Haynes P, Allen TD: Expression of a secretory product by microvillous and ciliated cells of the human endometrial epithelium in vivo and in vitro. Hum Reprod 1988, 3:927-934.
• [19]Simón C, Piquette GN, Francés A, El-Danasouri I, Irwin JC, Polan ML: The effect of interleukin-1 beta on the regulation of IL-1 receptor type I and IL-1 beta mRNA levels and protein expression in cultured human endometrial stromal and glandular cells. J Clin Endocrinol Metab 1994, 78:675-682.
• [20]Chomczynski P, Sacchi N: Single-step method for RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987, 162:156-159.
• [21]Smorodinsky N, Weiss M, Hartmann ML, Baruch A, Harness E, Yaakobovitz M, Keydar I, Wreschner DH: Detection of a secreted MUC1/SEC protein by MUC1 isoform specific monoclonal antibodies. Biochem Biophys Res Comm 1996, 228:115-121.
• [22]Hey NA, Aplin JD: Sialyl Lewis x and Sialyl Lewis a are associated with human endometrium. Glycoconj J. 1996, 13:769-779.
• [23]Baruch A, Hartmann M, Yoeli M, Adereth Y, Greenstein S, Stadler Y, Skornik Y, Zaretsky J, Smorodinsky NI, Keydar I, Wreschner DH: The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein. Cancer Research 1999, 59:1552-1561.
• [24]Hilkens J, Ligtenberg MJL, Vos HL, Litvinov SV: Cell membrane-associated mucins and their adhesion modulating property. Trends Biochem Sci 1992, 17:359-363.
• [25]Wesseling J, van der Valk SW, Hilkens J: A mechanism for inhibition of E-cadherin-mediated cell-cell adhesion by the membrane-associated mucin episialin/MUC1. Mol Biol Cell 1996, 7:565-577.
• [26]Aplin JD: Adhesion molecules in implantation. Rev Reprod 1997, 2:84-93.
• [27]Quenby S, Vince G, Farquharson R, Aplin JD: Recurrent miscarriage: a defect in nature's quality control? Hum Reprod 2002, 17:1959-1963.
• [28]DeSouza MM, Surveyor GA, Price RE, Julian J, Kardon R, Zhou X, Gendler S, Hilkens J, Carson DD: MUC1/episialin: a critical barrier in the female reproductive tract. J Reprod Immunol 1999, 45:127-158.
• [29]Jones CJ, Ortiz ME, Croxatto HB, Manzur A, Slevin G, Aplin JD: Muc1 and glycan expression in the oviduct and endometrium of a New World monkey, Cebus apella. Biol Reprod 2001, 64:1535-1544.
• [30]Hoffman LH, Olson GE, Carson DD, Chilton BS: Progesterone and implanting blastocyst regulate MUC1 expression in rabbit uterine epithelium. Endocrinology 1998, 139:266-271.
• [31]Murphy CR: Understanding the apical surface markers of uterine receptivity: pinopods-or uterodomes? Hum Reprod 2000, 15:2451-2454.
• [32]Horne AW, White JO, el-N Lalani, Mobberley MA, Margara RA, Trew GH, Ryder TA: Analysis of epitopes on endometrial epithelium by scanning immunoelectron microscopy. Biochem Biophys Res Commun 2002, 292:102-108.
• [33]Meseguer M, Aplin JD, Caballero-Campo P, Cesar Martín J, Pellicer A, Simón C: Human endometrium mucin MUC1 is up-regulated by progesterone and down-regulated in vivo by the human blastocyst. Biol Reprod 2001, 64:590-601.