E European Society of Human Reproduction and Embryology
Human Reproduction Update 1999, Vol. 5, No.4 pp. 280–292
Mammalian reproductive tract mucins
Errin Lagow, Mary M.DeSouza and Daniel D.Carson1
Department of Biological Sciences, University of Delaware, 115 Wolf Hall, Newark, DE 19707, USA
Mucin glycoproteins are major constituents of the glycocalyx that covers mucosal epithelium. Two broad classes of
mucins exist: membrane-associated and secretory. Of the secreted mucins, those with cysteine-rich regions are thought
to polymerize through disulphide bonds. Among these gel-forming mucins are MUC2, MUC5AC, MUC5B and possibly
MUC6. MUC7 lacks cysteine-rich domains and is thought to be secreted as a soluble monomer. Incomplete sequence
information prevents classification of other mucins. Tandem repeats of amino acids rich in serine, threonine and proline
are a common element in mucin core proteins, giving rise to relatively rigid, linear molecules with great potential for
glycosylation. Ten distinct mucin genes have been identified in humans so far. Patterns of expression vary greatly. While
MUC9, or oviductin, appears to be restricted to oviduct, the transmembrane mucin MUC1 is widely expressed. Proven
functions for the different mucins are largely unknown, although potential functions are addressed in this review.
Genetic and protein sequence information and expression profiles are also summarized, followed by a description of
mucin assembly. Special attention is given to mucin expression in male and female reproductive tracts.
Key words: cell adhesion/mucin/protection from infection/reproductive tract
TABLE OF CONTENTS
Introduction
Mucin genes and proteins
Mucin assembly
Mucin functions
Mucin expression in the reproductive tract
Summary and future directions
Note added in proof
References
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280
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285
286
289
289
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Introduction
The reproductive tract mucosa must permit gamete transport
and, in the case of the uterus, also embryo implantation and
placental development. These processes, however, occur
relatively infrequently. In contrast, reproductive tract mucosa
must persistently provide protection against infection. Part of
the protective functions of these tissues is provided by
specialized lymphoid tissues along with a standard
complement of lymphocytes and phagocytic cells (Parr and
Parr, 1986). Nonetheless, a major barrier to infection prevents
pathogenic colonization, and mucin glycoproteins expressed at
the apical surfaces of epithelia are believed to play major roles
as barrier molecules in mucosa. In addition to providing
lubrication of epithelial surfaces and preventing tissue
dehydration (Jentoff, 1990; Devine and McKenzie, 1992),
1To
evidence suggests that mucins may also protect proteins and
cells from proteolysis (Jentoff, 1990), protect tissues from
microbial attack (Lamblin and Roussel, 1993), modulate cell
attachment (Hilkens et al., 1992; Ligtenberg et al., 1992;
Kemperman et al., 1994; Wesseling et al., 1995; Hey and
Aplin, 1996; Zhang et al., 1996), and inhibit immune cell
function (Fung and Longenecker, 1991; Ogata et al., 1992;
Gimmi et al., 1996; see Table I). In the discussion below, we
will first consider basic aspects of the structure and assembly of
mucin glycoproteins, as well as their proposed functions. The
expression of mucins and mucin genes in the mammalian
reproductive tract as well as potential specialized functions that
these glycoproteins perform in these tissues will be considered.
Mucin genes and proteins
Mucins are defined as proteins that are heavily substituted with
oligosaccharides in O-linkage to serine or threonine residues.
However, while all mucins described are O-glycosylated
glycoproteins, not all O-glycosylated proteins are mucins
(Van Klinken et al., 1995). Mucin core proteins typically
contain a series of tandem repeat domains enriched in serine,
threonine and proline residues (see Table II). Except for
MUC5B, many human mucin genes are polymorphic. Allelic
variation observed in these genes is normally due to variable
numbers of tandem repeats (Debailleul et al., 1998). The
nomenclature adopted for mucin genes is MUC followed by a
whom correspondence should be addressed: Fax: (302) 831 2281; Tel: (302) 831 6977; e-mail: [email protected]
Mammalian reproductive tract mucins
number reflecting the order in which the particular mucin gene
was discovered. A total of 10 mucin genes have been
unequivocally identified; however, there are probably at least
several more (see below). MUC2, MUC5AC, MUC5B and
MUC6 are all located on chromosome 11p15 and their proteins
have cysteine-rich domains similar to those in von Willebrand
factor (vWF) that may participate in intermolecular disulphide
bonds, ultimately forming the viscous gel covering most
luminal surfaces (Desseyn et al., 1997a; Gipson and Inatomi,
1997; Keates et al., 1997). Cysteines within the C-termini of
these gel-forming mucins are conserved in number and in
spacing. This feature is shared with vWF and growth factors
such as transforming growth factor β (TGFβ) and is predicted
to form a specific tertiary structure. Referred to as a cystine
knot, this putative structure would result from the formation of
three intramolecular disulphide bonds among six conserved
C-terminal cysteines (McDonald and Hendrickson, 1993;
Meitinger et al., 1993). The functional significance of this
structure is unknown. Alternatively, MUC7 is secreted as a
soluble, non-gel-forming monomer (Bobek et al., 1993).
Further information is needed to categorize accurately MUC3,
MUC4 and MUC8 genes and their proteins.
Table I. Characteristics of mucin tandem repeats (TRs)
Mucin
TR unit
%Thr
%Ser
%Pro
Number of TRs
MUC1
MUC2
20 aa
23 aa
15
55–60
10
0–3
25
22
20–125
100 in most
common allele
MUC3
59 aa
17 aa
16 aa
5 aa
8 aa
29 aa
29
25
14
41
29
6
25
19
13
sequence is unpublished
63
25
13
repeats are irregular
11 in each
super-repeat
MUC4
MUC5AC
MUC5B
MUC6
MUC7
169 aa
23 aa
31
22
18
17
15
35
MUC8
41 aa
13 aa
15 aa
10
15
20
12
8
7
12
8
11
30
18.5
MUC9
SMC
117–124 aa
7.3
Table II. Suggested mucin functionsa
Lubrication, tissue hydration
Protection of proteins and cells from proteolysis
Protection from microbial attack
Inhibition of cell attachment
Promotion of cell attachment
Inhibition of immune cell function
aFor
references, see text.
6 (in 1st
cDNA cloned)
4 (in 1st
cDNA cloned)
14 in ASGP-1
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A transmembrane sialomucin complex (SMC) composed of
two subunits, ascites sialoglycoprotein (ASGP)-1 and -2, has
been identified in rat, and similarities exist between MUC1 and
SMC with regard to protein structure and processing (Gendler
and Spicer, 1995; Rossi et al., 1996); See Note added in proof.
MUC1 is one of the few known transmembrane mucins in
humans. Forms of MUC1 exist that lack either the ectodomain
(Zrihan-Licht et al., 1994) or the cytoplasmic tail (Williams
et al., 1990); however, it is not clear whether these result from
alternative mRNA splicing events or proteolytic cleavage
events. The molecular weight of the core protein of MUC1 is
calculated to be 120–225 kDa, while the mature glycosylated
protein has a range of 250–500 kDa (Lancaster et al., 1990;
Gendler et al., 1991; Gendler and Spicer, 1995). A MUC1
molecule can contain 20–125 tandem repeats and may be
composed of 60–80% carbohydrate (Gendler et al., 1991;
Gipson and Inatomi, 1997). Other names for MUC1 include
polymorphic epithelial mucin (PEM), episialin, peanut
lectin-binding urinary mucin, DF3 antigen (recognized by DF3
monoclonal antibody), epithelial membrane antigen (EMA)
and HMFG (human milk fat globule) antigen (Gum et al.,
1994). The genomic sequence of MUC1 spans 4–7 kilobases,
contains seven exons for a transcript of 2.5–8.8 kilobases, and
is located on chromosome 1q21–24 in humans (Lancaster
et al., 1990). Most of the mucins discovered after MUC1 have
been classified as secretory because of their expression by
simple secretory epithelia, although the complete cDNA
sequences are known only for MUC2, MUC7 and MUC9.
MUC2 initially was cloned from a human intestine cDNA
library (Gum et al., 1989, 1994) and has been detected in colon,
small intestine and airways (Gum et al., 1994). The complete
cDNA sequence of 15 563 base pairs encodes more than 5100
amino acids with four 350-amino acid, cysteine-rich repetitive
elements (D1–D4) similar to the four D-domains of vWF
(Gum et al., 1994; see Figure 1). Following the three
N-terminal D-domains is a mucin-like domain defined by
Thr/Ser/Pro(TSP)-rich irregular repeats and a variable-length
region of 23-amino acid tandem repeats (see Figure 1). The
TSP-rich region and variable-length region together constitute
more than half the length of MUC2 protein encoded by the
most common allelic form of the gene, which contains
approximately 100 tandem repeats (Gum et al., 1994).
Transcripts of 14–16 kilobases have been reported for MUC2
due to allelic variation in the number of tandem repeats
(Debailleul et al., 1998).
Partial cDNA sequences have been reported for MUC3,
cloned from a human small intestine library and localized to
chromosome 7q22 (Gum et al., 1990; Fox et al., 1992;
Van Klinken et al., 1997). Over 2 kilobases of continuous
cDNA sequence encoding 650 amino acids was found to
contain a mucin-like, non-repetitive region, rich in serine
(20%), threonine (27%) and proline (11%), flanked by two
types of tandem repeat domains (Yan et al., 1990). cDNA
clones of the 177-base pair (59-amino acid) and 51-base pair
282
E.Lagow, M.M.DeSouza and D.D.Carson
Figure 1. Encoded domains of mucin gene products. Lengths of cDNAs and encoded proteins are indicated. ASGP = ascites sialoglycoprotein;
CK = putative cystine knot; CT = cytoplasmic tail; EGF = epidermal growth factor-like domain; SP = signal peptide; TM = transmembrane
domain; TRs = tandem repeats; TSP = threonine-serine-proline. D-domain, D4-like domain and C-like domain = Cys-rich domains similar to
those in von Willebrand factor (vWF). See text for further detail and references.
(17-amino acid) tandem repeat regions indicate that these
regions are at least 2.3 and 4 kilobases in length respectively
(Van Klinken et al., 1997). Potential N-glycosylation sites were
found occasionally within both regions, but not within the
consensus sequence for either (Van Klinken et al., 1997). Also,
one cysteine was found between the non-repetitive region and
the 17-amino acid tandem repeat region (Van Klinken et al.,
1997). In addition to small intestine, MUC3 has been detected
in colon and gallbladder (Gum et al., 1990; Van Klinken et al.,
1997).
Cloned from a tracheobronchial cDNA library (Porchet
et al., 1991) and localized to chromosome 3q29 (Seregni et al.,
1997), MUC4 is distinguished from other mucins by tandem
repeats of 48 base pairs, encoding a repeating peptide of
16 amino acids rich in serine (19%), threonine (25%) and
proline (13%) (Porchet et al., 1991), and also by tandem
repeats of 15 base pairs, perfectly conserved and extending for
at least 4 kilobases (Porchet et al., 1995). A recently obtained 5′
sequence revealed a signal peptide similar to that of the SMC
subunit ASGP-1 (Nollet et al., 1998). In-situ hybridization and
Northern blot analysis demonstrated expression of MUC4 in
bronchus, prostate, endocervix (Porchet et al., 1995) and
conjunctival epithelium (Gipson and Inatomi, 1997), with
weak expression in small intestine, colon and gastric
epithelium (Porchet et al., 1995). The MUC4 gene is highly
polymorphic in humans due to variable numbers of tandem
repeats (Debailleul et al., 1998).
Peptide fragments and partial cDNA clones encoding
MUC5AC have been isolated and analysed (Rose et al., 1989;
Meerzaman et al., 1994; Guyonnet-Duperat et al., 1995;
Lesuffleur et al., 1995). According to biochemical and molecular
analysis, MUC5AC appears to have mucin-like, TSP-rich,
glycosylated domains interrupted by Cys-rich, poorly
glycosylated domains (Rose et al., 1989; Guyonnet-Duperat
et al., 1995). The TSP-rich regions consist of either repetitive
sequences of 24-base pair (8-amino acid) tandem repeats or
non-repetitive sequences (Guyonnet-Duperat et al., 1995). The
Cys-rich domains are 130 amino acids each, with ten conserved
cysteines per domain (Guyonnet-Duperat et al., 1995; see
Figure 1). Three different C-termini have been reported,
including a 436-base pair cDNA clone, containing tandem
repeats of 24 base pairs (8-amino acids) followed by nine stop
codons and a polyadenylation sequence (Guyonnet-Duperat
et al., 1995). Independently, two other groups isolated cDNA
Mammalian reproductive tract mucins
clones greater than 3 kilobases that are 98.6% identical in
nucleotide sequence, but due to single amino acid differences,
changes in reading frame cause the deduced peptides to have
four regions of low similarity, one being an additional
C-terminal sequence (Meerzaman et al., 1994; Lesuffleur
et al., 1995; see Figure 1). In spite of these differences, both
sequences are cysteine-rich and display three short conserved
sequences and potential N-glycosylation sites that may play a
role in polymerization (Meerzaman et al., 1994; Lesuffleur
et al., 1995). Cysteine-rich sequences induce polymerization
by forming disulphide bonds. Expression of MUC5AC has
been detected by in-situ hybridization and Northern blot
analysis most strongly in bronchial epithelium and submucosal
glands, surface mucous cells of gastric epithelium (Porchet
et al., 1995), and conjunctival goblet cells of the eye (Gipson
and Inatomi, 1997), with moderate expression in endocervix
and weak expression in gallbladder (Porchet et al., 1995).
Genomic sequences encoding over 20 kb of MUC5B
transcript have been reported (Troxler et al., 1995; Desseyn
et al., 1997a,b; Keates et al., 1997; Nielsen et al., 1997). This
mucin was initially referred to as human gallbladder mucin or
high-molecular weight salivary mucin MG1. MUC5B contains
a very large central exon of 10 713 base pairs encoding a
peptide of 3570 amino acids (Desseyn et al., 1997b). The
peptide contains four 528-amino acid super-repeats, each
composed of three subdomains: 11 irregular 87-base pair
repeats, 111 amino acids of mucin-like, TSP-rich nonrepetitive sequence, and a cysteine-rich subdomain of
108 amino acids with similarity to cysteine-rich sequences in
MUC2 and MUC5AC (Desseyn et al., 1997b; see Figure 1).
This super-repeat is the largest repeat known of all mucin genes
(Desseyn et al., 1997b). Two different C-termini have been
published for MUC5B. Initially, 10 690 base pairs of genomic
sequence was described encoding an 808-amino acid peptide
that contains several regions similar to corresponding
sequences in other 11p15 mucin genes and in vWF (Desseyn
et al., 1997a; see Figure 1). Subsequently, genomic clones were
reported encoding 983 amino acids of C-terminal sequence
(Keates et al., 1997). The two prospective C-termini display
overall similarity to each other, with differences in the number
of potential N-glycosylation sites and in vWF C-like (similar to
one of the cysteine-rich C–domains of vWF) domains
(Desseyn et al., 1997a; Keates et al., 1997). The MUC
11p15-type subdomain shows similarity with respect to
cysteine residues in MUC2, MUC5AC and MUC5B (Desseyn
et al., 1997a). Several domains in these mucins display
cysteines conserved in human vWF, although representation
varies between prospective C-terminal sequences for
MUC5AC and MUC5B (Desseyn et al., 1997a). MUC5B
expression has been detected strongly in all mucous cells of
salivary glands (Troxler et al., 1995; Nielsen et al., 1997),
bronchial submucosal glands, and gallbladder epithelium and
glands, with weak expression in endocervix (Porchet et al.,
1995). Biochemical studies of MUC5B demonstrated that the
283
mature glycoprotein is >1000 kDa, comprised of
approximately 15% protein and 78% carbohydrate, and
probably exists as an oligomer (Bobek et al., 1993). Also, the
MUC5B gene is unique among the human mucins since it does
not appear to be polymorphic (Debailleul et al., 1998).
MUC6 (human gastric mucin) was partially cloned from a
gastric cDNA library (Toribara et al., 1993). cDNA sequences
include a tandem repeat region of 507-base pairs encoding an
amino acid sequence with repeat units rich in threonine (31%),
serine (18%) and proline (15%) (Yao et al., 1997), in addition
to a C-terminal sequence beginning with a series of 169-amino
acid tandem repeats followed by a 270-amino acid mucin-like,
TSP-rich (61%) non-repetitive region, ending with a Cys-rich
region similar to the extreme C-terminus of vWF, based on
conservation of the 11 invariant cysteine residues of the
putative cystine knot (Toribara et al., 1997; see Figure 1).
Within the gastrointestinal tract, MUC6 is expressed in mucous
neck cells of the fundus, submucosal glands in the antrum and
cardia, and Brunner’s glands of the duodenum, with weak
expression in terminal ileum and right colon (Toribara et al.,
1993, 1997). MUC6 has also been detected in gallbladder,
pancreas, seminal vesicles and the female reproductive tract
(Toribara et al., 1997).
MUC7, or low-molecular weight human salivary mucin
MG2, is a 120–150 kDa glycosylated protein with a 39 kDa
core protein. MUC7 was cloned initially from a human
submandibular gland cDNA library and mapped to
chromosome 4 (Bobek et al., 1993). The protein is composed
of 30% protein and 68% carbohydrate, and exists as a soluble,
non-gel-forming monomer secreted by mucous acinar cells of
sublingual, submandibular and labial salivary glands. The first
20 encoded amino acids of MUC7 are hydrophobic and are
thought to constitute the signal peptide. The tandem repeat
domain consists of 23-amino acid (69-base pair) repeat units
rich in threonine (22%), serine (17%) and proline (35%) and is
flanked by unique 5′ and 3′ regions containing four and one
potential N-glycosylation sites respectively. Although six
tandem repeats were found in the cloned MUC7 sequence, the
gene may be polymorphic, as suggested by Southern blot
analysis. Two cysteines are present in the unique 5′ region of
MUC7 and may participate in an intramolecular disulphide
bond since MUC7 exists as a monomer. Even though part of the
MUC7 cDNA contains a start codon with a strong Kozak
consensus sequence for translation initiation, as well as an
in-frame stop codon, there is some doubt that the actual 5′ end
of the mRNA has been determined.
C-terminal sequence information for the protein has been
published for MUC8, a major airway mucin originally cloned
from a normal human tracheal expression library (Shankar
et al., 1997). A total of 942 base pairs of continuous cDNA
sequence includes a region of near-perfect, 41-base pair
tandem repeats that encode two types of peptide repeats
consisting of 41 and 13 amino acids, followed by a unique,
non-repetitive sequence of 30 amino acids. Northern blot
284
E.Lagow, M.M.DeSouza and D.D.Carson
analysis and immunohistochemical studies demonstrate that
MUC8 is expressed in stomach, submucosal glands of the
trachea, testis, placenta, endometrium and cervix, with
weak-to-undetectable levels in epididymis, seminal vesicle,
ovary, Fallopian tube and uterus (D’Cruz et al., 1996). The
MUC8 gene was localized to chromosome 12q24.3 (Shankar
et al., 1997).
MUC9, which encodes the oviduct-specific glycoprotein
oviductin, is 2216 base pairs in length (Arias et al., 1994;
Lapensee et al., 1997). The cDNA has an open reading frame
of 1962 base pairs encoding a 654-amino acid core protein with
a calculated molecular mass of 72.9 kDa (120 kDa when
glycosylated) (Arias et al., 1994). The last 510 base pairs of
oviductin cDNA contain three divergent 45-base pair tandem
repeats followed by two partial repeats, encoding a peptide
repeat unit of 15 amino acids composed of approximately 20%
threonine, 7% serine and 11% proline (Arias et al., 1994).
Similar repeats were found also in C-termini of hamster, mouse
and baboon oviductin (Arias et al., 1994; Suzuki et al., 1995).
Five cysteine residues are found widely spaced within the 484
amino acids preceding the tandem repeats, and a string of 11
hydrophobic residues at the N-terminal end of the protein may
represent a signal peptide (Arias et al., 1994).
Several mucins have been identified in species other than
human beyond the orthologues of mucins already mentioned.
Porcine submaxillary mucin contains a large tandem repeat
domain of 130–200 repeats of 81 amino acids flanked by
mucin-like regions rich in threonine, serine and proline
(reviewed in Gendler and Spicer, 1995). Several
N-glycosylation sites are also present, in addition to a
cysteine-rich extreme C-terminus, a feature conserved among
secreted mucins such as bovine submaxillary mucin-like
protein, and the frog integumentary mucins. Biochemical
studies indicate that porcine submaxillary mucin has no
secondary structure except for a globular tail formed by
disulphide bonds among cysteines. Partial cDNA sequence of
bovine submaxillary mucin has been obtained encoding
563 amino acids, 339 of which are mucin-like sequence (39%
serine and threonine, 4% proline), followed by a cysteine-rich
domain of 244 amino acids (11% cysteine, 12% serine and
threonine). This sequence is similar to porcine submaxillary
mucin, but the actual C-terminus of bovine submaxillary mucin
has yet to be determined, and no biochemical analysis has been
performed (reviewed in Gendler and Spicer, 1995).
The frog integumentary mucins (FIM) are produced by
merocrine mucous glands within the skin of Xenopus laevis
(Gendler and Spicer, 1995). FIM-B.1, the only mucin gene
whose tandem repeat sequence is divided by introns, is
composed mostly of acidic repeats of 11 amino acids with
many O-glycosylation sites. Interrupting the repeats is a region
similar to the short conserved region seen in the complement
receptor family that contains four conserved Cys-Phe-Tyr-GlyTrp-Pro. It has been suggested that this short conserved region
serves to disrupt bacterial adhesion to the host by competitive
inhibition, as this region is an attachment site for many bacteria
(Gendler and Spicer, 1995). FIM-A.1 (spasmolysin) consists of
a 43 kDa core protein (130 kDa mature glycosylated form) that
contains 13 Thr-rich repeats of nine amino acids, seven repeats
of sequence Glu-Thr-Thr-Thr, and four P-domains that are
strings of approximately 50 amino acids with six invariant Cys
forming three intramolecular disulphide bridges (Gendler and
Spicer, 1995). Spasmolysins generally inhibit gastrointestinal
motility and induce gastric secretion, and stimulate growth of
colon and breast tumours in vitro. Partial sequencing of
FIM-C.1 reveals three semi-repetitive Thr-rich clusters and six
P-domains. The gene is polymorphic due to variable lengths of
Thr-rich domains, and is expressed in cone cells of mucous
glands, the only place lacking FIM-A.1.
Mucin assembly
As mentioned above, mucin glycoproteins are heavily
substituted with O-linked oligosaccharides that may constitute
most of the mass of the glycoprotein (Jentoff, 1990; Carraway
and Hull, 1991). The constituent O-linked oligosaccharides are
linked through N-acetylgalactosamine at their reducing termini
to proteins via the hydroxyl groups of serine or threonine
residues. Hundreds of O-linked oligosaccharide structures
have been determined by various techniques including
glycosidase sensitivity, nuclear magnetic resonance (NMR)
and mass spectrometry. The core N-acetylgalactosamine is
substituted with galactose in either β1→3 or β1→4 linkage.
Additional modifications give rise to structures that are
branched and variously substituted with N-acetylglucosamine,
galactose, fucose, sialic acids or sulphate (Carraway and Hull,
1991; Kobata and Takasaki, 1992). Some of these structures are
found in a diverse array of cells and tissues, while others are
only transiently expressed and highly localized in adult or
developing tissues (Muramatsu, 1988). Many monoclonal
antibodies have been generated which contain O-linked
oligosaccharide determinants as all or part of their structure.
Expression of certain mucin oligosaccharide structures may
serve as useful markers of developmental transitions
(Muramatsu, 1988) or the presence of certain tumours (Ho and
Kim, 1991; Devine and McKenzie, 1992). In addition, mucin
oligosaccharides may present motifs critical for cell
recognition processes, e.g. selectin ligands (Lasky, 1992).
Like other secretory or cell surface proteins, mucin core
proteins are synthesized in the rough endoplasmic reticulum
and traffic to the Golgi apparatus where the O-glycosylation
reactions occur, including the initial addition of the core
N-acetylgalactosamine residue (Hull et al., 1991; Roth et al.,
1994; Pimental et al., 1996). The primary amino acid sequence
requirements for O-glycosylation of mucin core proteins
appear to be fairly promiscuous and are poorly understood, in
spite of a great deal of research to define acceptor site
specificities. The linkage serine/threonine residues are usually
flanked by proline residues in the –6, –1 or +3 positions
Mammalian reproductive tract mucins
(O’Connell et al., 1991). Multiple UDP-GalNAc:protein
GalNAc transferases can glycosylate both serine and threonine
residues in synthetic peptides; however, threonines seem to be
the preferred sites (Wang et al., 1992; Wandall et al., 1997).
Recent studies reveal that only a limited number of potential
acceptor sites in MUC1 tandem repeat regions are glycosylated
in vitro (Nishimori et al., 1994); however, almost all potential
O-glycosylation sites in MUC1 can be O-glycosylated in vivo,
although all such sites may not be glycosylated in an individual
MUC1 molecule (Müller et al., 1997). Moreover, the type and
degree of O-glycosylation of a given mucin core protein can
vary greatly in different cells. For example, MUC2
oligosaccharides are heavily sialylated in the small intestine
and heavily sulphated in the large intestine (Karlsson et al.,
1997). Furthermore, tumour cells appear to express
underglycosylated forms of mucins relative to normal cells
(Ho and Kim, 1991; Devine and McKenzie, 1992). Following
these terminal glycosylation reactions, mucins then transit to
the cell surface either for residence at the plasma membrane or
secretion. Estimated transit times from the sites of synthesis to
the cell surface range from 0.5 to 2.5 h (Linsley et al., 1988;
Dohi et al., 1993; Litvinov and Hilkens, 1993; Pimental et al.,
1996).
Secretory mucins are released where they can form
extremely large and viscous gels held together by disulphide
bonds (Forestner, 1995). Such mucins are generally cleared by
net fluid flow through the lumina of various mucosa (Forestner,
1995). Integral cell surface mucins are retained at the external
surface of the plasma membrane via transmembrane domains
of their protein cores (Carraway and Hull, 1991). In polarized
cells, mucins are primarily expressed at the apical cell surface
(Jentoff, 1990; Carraway and Hull, 1991). While MUC1 is the
only human mucin known to be membrane-spanning, a second
transmembrane mucin, SMC, has been described in rat (Sheng
et al., 1992; Wu et al., 1994; Rossi et al., 1996). The SMC
heterodimer is synthesized as a single peptide precursor that is
cleaved into two subunits: ASGP-1, the glycosylated
mucin-like portion; and ASGP-2, the membrane-associated
part of the heterodimer (Rossi et al., 1996). Studies of MUC1
indicate that membrane-sorting signals may occur in the
transmembrane or membrane-proximal ectodomain sequences
of the protein core (Pemberton et al., 1996). Metabolic
half-lives of Muc1 and other cell-associated mucins in normal
mouse uterine epithelial cells were estimated to be
approximately 16 h (Pimental et al., 1996). Catabolism of these
mucins may, in part, be due to endocytosis and lysosomal
degradation; however, a large fraction of such mucins are
removed by release of the ectodomain from the cell surface
(Boshell et al., 1992; Pimental et al., 1996). It is possible that
this release is via a proteolytic mechanism, but this has not been
rigorously demonstrated. Nonetheless, mucin ectodomain
release apparently does result in separation from the
membrane-spanning region of the protein core (Boshell et al.,
1992; Pimental et al., 1996); however, these transmembrane
285
domains do not accumulate in cells, suggesting that they are
targeted for degradation following separation from the
ectodomain. There also is evidence that transmembrane
mucins can be recycled after endocytosis (Hull et al., 1991;
Litvinov and Hilkens, 1993). These observations indicate that
at least a subpopulation of mucins can be modified after they
are initially assembled and transported to the cell surface.
In spite of the extraordinary resistance of mucins to
enzymatic attack, both bacteria (Abdullah et al., 1992) and
mammalian tissues (Slomiany et al., 1993) secrete enzymes
that have the ability to digest mucins. These enzymes may act
on either secreted, soluble mucins or mucin ectodomains as
well as cell surface forms. In the case of bacteria,
mucin-degrading enzymes may aid in escape from mucus gels
or penetration to the cell surface (see below). The physiological
function of mammalian-secreted, mucin-degrading enzymes is
not clear; however, some data indicate that the products of these
digestions bind microbes more effectively than the intact
mucins (Slomiany et al., 1993). Therefore, production of
mucin-degrading enzymes may promote antibacterial activities
rather than function in mucin catabolism.
Mucin functions
As noted above, mucin glycoproteins are very large, highly
hydrated structures. As such, they can function as lubricants
and prevent dehydration of luminally disposed cell surfaces
(Jentoff, 1990; Devine and McKenzie, 1992). A number of
proteins not classically thought of as mucins, e.g. low-density
lipoprotein (LDL) receptor, contain regions heavily substituted
with O-linked oligosaccharides. The dense packing of the
oligosaccharides protects these regions of proteins from
proteolytic attack (Jentoff, 1990). In classic mucins, this
principle is extended. Virtually all of the protein core of soluble
mucins and the extracellular domain of transmembrane mucins
are substituted with O-linked oligosaccharides, making them
extremely resistant to proteolysis.
Mucins have classically been attributed the role of a
protectant against bacterial colonization and/or infection
(Cohen et al., 1984; Lamblin and Roussel, 1993). Bacterial
access to mucosa comes from the external environment via
ingestion, respiration or coital activity. Given the diversity of
the organ systems involved, an underlying characteristic holds
firmly, that of a luminal epithelial layer which expresses and is
covered by a thick gelatinous mucin layer in which bacteria are
trapped (Lamblin and Roussel, 1993; Slomiany et al., 1996).
Subsequently, immunological responses such as phagocytosis
and outflow from the organ system neutralize and remove
bacteria from the host. This process is quite evident in the
respiratory system where ciliary beating removes
mucin-trapped bacteria from the bronchial passages and
trachea and releases them as sputum (Lamblin and Roussel,
1993). Given the extreme diversity of bacteria present in the
environment, an equally diverse method of entrapment is
286
E.Lagow, M.M.DeSouza and D.D.Carson
necessary. In most bacteria thus far examined, bacterial
proteins (adhesins) act as receptors for carbohydrate epitopes
expressed on mucins. Often, these interactions occur between
selective sulphated or sialylated carbohydrate moieties. For
example, in such diverse tissues as vagina, mouth and small
intestine, Escherichia coli Type I, S and K88 fimbriae all
recognize carbohydrate structures expressed on mucins as their
cognate ligands (Erickson et al., 1992; Schroten et al., 1993;
Venegas et al., 1995). In addition, in the respiratory system
both Staphylococcus aureus and Pseudomonas aeruginosa
have been shown to bind to mucin carbohydrates (Scharfman
et al., 1996; Trivier et al., 1997). More recently, the bacteria
that can cause ulcers, Helicobacter pylori, have been shown to
be inhibited from binding to acidic glycosphingolipids on
gastric epithelial cells by gastric sulphomucins (Veerman et al.,
1997). Even with the multitude of bacteria attempting
colonization within the host, the diversity of carbohydrate
chains expressed on mucin proteins severely limits the ability
of different bacteria to escape capture, though certain bacteria
are able to penetrate the mucus layer and interact directly with
the surface of epithelial cells (Draper et al., 1980). The method
by which transmembrane mucins protect cells from bacterial
infection is less clear, since these molecules would be expected
to promote bacterial attachment to the mucosal surface. It is
possible that binding to cell surface mucins still prevents
binding to more proximal carbohydrate-bearing cell surface
components, e.g. most glycoprotein receptors and
gangliosides. It also is possible that bacterial binding stimulates
release of mucin ectodomains, thereby preventing surface
adherence.
The large, extended structures of cell surface mucins also
limit accessibility to other cell surface components. The
abundance of cell surface mucins, as well as the number of
tandem repeat motifs, play important roles in such activities.
Deletion of tandem repeat domains demonstrates that mucins
must extend at least 50–200 nm from the cell surface to provide
an effective barrier (Wesseling et al., 1996; Komatsu et al.,
1997). The presence and structure of oligosaccharide chains
also play an important role in this regard. Inhibitors of O-linked
oligosaccharide assembly cause production of mucin
glycoproteins with truncated or aberrant structures (Kuan et al.,
1989). Uterine epithelial cells treated with such inhibitors
display increased accessibility of apically disposed cell surface
components to both carbohydrate ligands and enzymes
(Valdizan et al., 1992). Similarly, it is believed that the
propensity of many tumour cells to express high levels of
mucins aids in their protection from the host immune system
(Sherblom and Moody, 1986; Devine and McKenzie, 1992;
van de Weil-van Kemenade et al., 1993). In addition to
preventing sterically immune cells from attacking the tumour
cell surface by steric hindrance, mucins also may repress
immune cell activities or stimulate apoptosis of immune cells
(Fung and Longenecker, 1991; Ogata et al., 1992; Gimmi
et al., 1996).
From the above, it can be reasoned that one result of
high-level mucin expression is the creation of an enzymatically
resistant, non-adhesive cell surface. In fact, mucins limit access
to host cell receptors and severely impair cell–cell and
cell–extracellular matrix adhesion (Hilkens et al., 1992;
Ligtenberg et al., 1992; Kemperman et al., 1994; Wesseling
et al., 1995). Paradoxically, mucins also may promote cell
adhesion. Selectin ligands are carried by mucin glycoproteins
(Hey and Aplin, 1996; Zhang et al., 1996); however, there is
little evidence that selectin ligands occur or function
physiologically at extravascular sites. Nonetheless, the
presence of mucins does not necessarily imply nonadhesiveness, in all cases.
Mucin expression in the reproductive tract
Relatively little is known about mucin expression in the male
reproductive tract. Among male reproductive tract tissues, the
prostate has been studied most, in this regard. It is clear that
both normal and malignant prostate epithelia display
histologically detectable mucins (Gal et al., 1996); however,
there is a shift from mucins bearing neutral oligosaccharides
toward those bearing acidic oligosaccharides during
conversion to a malignant state (Sentinelli, 1993; Goldstein
et al., 1995). Among integral membrane mucins, MUC1 is
highly expressed in the prostate (Ho et al., 1993; Gold et al.,
1994). Northern blot analyses failed to detect transcripts for the
genes MUC2 or MUC3 encoding secreted mucins, in either
normal or malignant prostate (Ho et al., 1993), although
antibodies directed against a peptide motif of the tandem repeat
region of MUC2 did react with this tissue (Durrant et al., 1994).
It is possible that MUC2 is transported to the prostate, or that
protein bearing a related epitope occurs in this tissue. A
recently discovered gene encoding a protein with multiple
membrane-spanning domains and mucin-like regions, HE6, is
highly expressed in the epididymis (Osterhoff et al., 1997).
Surprisingly, a few reports indicate that mucins (MUC8) are
present on spermatozoa (D’Cruz et al., 1996). It is possible that
a mucin coat on spermatozoa might reduce sperm adhesion
during its transit through the male and/or female reproductive
tract. In fact, mucins have a significant effect on sperm
transport through the cervical canal (as reviewed by Moghissi,
1972; Eriksen et al., 1998).
Considerably more studies have been performed on mucin
expression in the female reproductive tract, including ovaries,
oviduct or Fallopian tube, uterus, cervix and vagina. The
physiology and morphology, as well as glycoprotein
biosynthetic capacity, of female reproductive tract tissues are
strongly influenced by steroid hormones (Carson et al., 1990;
Surveyor et al., 1995; Hoffman et al., 1998). In addition,
different regions of the female reproductive tract respond
distinctly to steroid hormones. Therefore, knowledge of mucin
expression in one region of the female reproductive tract is not
necessarily predictive of expression in another region. In the
Mammalian reproductive tract mucins
complex tissue of the uterus, two types of epithelia, i.e. luminal
and glandular, occur that also display regional distinctions.
Thus, it is important to determine the stage of the oestrous or
menstrual cycle from which tissues are prepared and, in the
case of the uterus, the type of epithelium examined. These
factors are not always clearly defined in the reports that have
appeared.
Zona pellucida glycoproteins are produced in the ovary and
surround mature ova (Wassarman and Litscher, 1995). Several
types of studies indicate that the oligosaccharides of these
glycoproteins play key roles in spermatozoa–egg recognition
(Wassarman, 1995; Wassarman and Litscher, 1995). There is
little information on other mucin glycoproteins expressed in the
ovary. Mucin biosynthetic enzymes also are found in normal
ovarian tissues (Yazawa et al., 1986). Thus, the ovary is capable
of assembling mucin glycoproteins; however, it is less clear
whether mucin core proteins other than those for zona
glycoproteins are expressed in this tissue. Conflicting reports
have appeared on MUC1 expression in normal human ovary,
perhaps due to differential specificities of the monoclonal
antibodies used in these studies (Girling et al., 1989; Ho et al.,
1993; Tashiro et al., 1994). Little Muc1 expression has been
observed in the mouse ovary using antibodies that recognize all
forms of Muc1 protein retaining a cytoplasmic tail (J.Julian and
D.D.Carson, unpublished observations). MUC2 does not
appear to be expressed in the human ovary (Tashiro et al.,
1994). In contrast, it is generally observed that MUC1 as well
as mucin-associated carbohydrate motifs are markedly
elevated in malignant human ovarian tissue and cell lines
(Girling et al., 1989; Yan et al., 1990; Ho et al., 1993; Tashiro
et al., 1994).
Unlike the ovary, the oviduct does typically express mucin
genes in a non-transformed state. Of the eight human mucin
genes cloned, the oviduct expresses only MUC1 in the
epithelium (Gipson et al., 1997). More recently, a secreted
oviductal protein, that has mucin-like properties is proposed to
represent a secretory-type mucin and has been tentatively
designated as MUC9 (Lapensee et al., 1997). The sequences of
this mucin-like protein, oviductin, in rodents and humans
displays the amino-acid tandem repeat motif common to
mucins. However, this motif is extremely divergent in the
sequence for the human protein and absent in large domestic
species (Malette et al., 1995). Unlike other mucin genes, which
are often expressed in several tissues, oviductin is exclusive to
the oviductal epithelium (Malette et al., 1995). This largemolecular weight glycoprotein is extensively O-substituted,
with approximately 50% or greater (depending on species) of
the molecular mass contributed by carbohydrates. In all species
thus far examined, oviductin has been found to be regulated by
the ovarian steroid hormones. It is not known if either MUC1 or
oviductin are regulated by steroidal hormones in humans. The
functions of either of these mucin proteins within the oviduct is
as yet unknown. Given that oviductin has been shown to
interact with both the ovulated oocyte and spermatozoa as they
287
traverse the oviduct, it has been postulated that this secreted
glycoprotein may play a role in oocyte fertilization
(Wassarman, 1995). Recently, it has been postulated (Lapensee
et al., 1997) that this protein may prevent ectopic pregnancy by
covering the epithelial cells. The same role is possible for
MUC1, given that it exhibits anti-adhesive characteristics in
vitro. Clearly, more investigation into the roles of both mucins
within the oviduct is necessary to determine their physiological
functions.
A number of studies have appeared on mucin expression in
the uterus. In all species examined to date, Muc1 is highly
expressed in the uterus. Curiously, not all human endometrial
cell lines express MUC1 and may even display ectopic
expression of airway mucins (Gollub et al., 1993; Hey and
Aplin, 1996). This raises concern over the validity of using
such cell lines for studies of regulation of mucin expression. In
many species, Muc1 is downregulated in the luminal
epithelium during the phase where embryo implantation
normally occurs (Surveyor et al., 1995; Bowen et al., 1996;
Hild Petito et al., 1996). This has led to the suggestion that
Muc1 serves as a barrier to embryo attachment under most
conditions (Surveyor et al., 1995). Rabbits also express very
high levels of Muc1 during the receptive phase; however,
Muc1 loss is restricted to the immediate site of embryo
attachment, suggesting that an anti-adhesive function is
conserved in this species (Hoffman et al., 1998). The
hypothesis that Muc1 prevents embryo attachment is supported
by the demonstration that RU486 both inhibits embryo
implantation and restores high-level Muc1 expression in mice
(Surveyor et al., 1995). Furthermore, while attachmentcompetent embryos fail to attach to polarized uterine epithelial
cells in vitro (Valdizan et al., 1992), they do so with high
efficiency if mucins are removed enzymatically or if Muc1 is
genetically ablated (DeSouza et al., 1999). Maintenance of
mucins at the apical surface of luminal uterine epithelial cells
may provide protection from infection until the point at which
the embryo is ready to attach. In fact, the uterus appears to be
generically more susceptible to invasion during the ‘receptive’
phase, as transplanted tumour cells more effectively penetrate
the endometrium at this time (Schlessinger, 1962; Maharajan
and Maharajan, 1986).
The major class of glycoproteins synthesized and
expressed at the apical surface of polarized uterine epithelia in
wild-type or Muc1 null mice is mucins (Valdizan et al., 1992;
Surveyor et al., 1995). Mucins also account for a major class
of glycoproteins synthesized by polarized uterine epithelia of
other species (Carson et al., 1988; Mani et al., 1992). In
contrast, mouse uterine epithelial cells cultured on tissue
culture plastic primarily synthesize N-linked glycoproteins.
Culture on matrigel-coated plastic is not sufficient to restore
the normal pattern of predominantly mucin-type glycoprotein
synthesis seen under polarizing conditions (Carson et al.,
1988). Therefore, adoption of a polarized state appears to be
an important factor for mucin expression by uterine epithelia,
288
E.Lagow, M.M.DeSouza and D.D.Carson
although the mechanism underlying this response is not clear.
Synthesis of mucins and many other classes of glycoproteins
is strongly regulated by steroid hormones in the uterus. These
responses are manifest both at the level of core protein mRNA
expression and the activities of various glycosyltransferases
(Carson et al., 1990 and references within; Surveyor et al.,
1995).
Muc1 accounts for less than 10% of the total complement of
mucin oligosaccharides in mice (Pimental et al., 1996). A
comprehensive survey of mucin gene expression
(MUC1–MUC7) revealed that only MUC1 and, to a lesser
extent, MUC6 are expressed in the human uterus (Gipson et al.,
1997). A recently identified gene encoding a respiratory tract
mucin, MUC8, has also been detected in human endometrium,
although the expression of this gene varied considerably from
patient to patient, perhaps due to differences in menstrual cycle
phase (D’Cruz et al., 1993). SMC also is expressed in rat uteri,
although it is not clear if this occurs in other species (McNeer
et al., 1998). Antibodies recognizing a mucin-like glycoprotein
of undefined core protein structure mouse ascites Golgi antigen
or MAG also react well with human endometrial glands, with
maximal reactivity during the receptive phase (Kliman et al.,
1995). It is not clear if the epitope recognized by MAG
antibodies represent pure carbohydrate determinants found on
many mucins, or peptide epitopes of known or novel mucin
core proteins.
A number of studies have focused on MUC1 protein and
mRNA expression using samples from women with
well-defined cycle phases. These studies generally reveal that
MUC1 levels increase during the mid-luteal (receptive) phase
(Hey et al., 1994, 1995; Aplin et al., 1996). Nonetheless, some
studies with MUC1-specific monoclonal antibodies suggest
that expression of some isoforms decreases during the
receptive phase (Rye et al., 1993). These studies primarily
described expression in glandular epithelium, the major
epithelial component of human uteri. Studies in the baboon
revealed that patterns of glandular and luminal Muc1
expression are quite distinct (Hild-Petito et al., 1996). Other
differences were noted between luminal and glandular MUC1
expression in women undergoing hormonal regimens for
oocyte donation (Meseguer et al., 1998a). Recently, studies
have been performed on human endometrial samples in the
mid-proliferative (non-receptive) and mid-luteal (receptive)
phases with clearly defined luminal epithelia (DeLoia et al.,
1998). These studies support the notion that MUC1 expression
is maintained throughout the epithelia in the receptive phase in
humans; however, as in the baboon, MUC1 shows regional
specialization in terms of its pattern of expression. This
specialization does not appear to occur at the level of MUC1
core protein expression, but rather at the level of carbohydrate
modifications. Luminal and glandular epithelium becomes
more modified with keratan sulphate and sialic acid residues
during the receptive phase (Hoadley et al., 1990; Aplin et al.,
1994). Such modifications can mask certain MUC1
ectodomain epitopes (Ho and Kim, 1991; Devine and
McKenzie, 1992; Ho et al., 1995) and may explain earlier,
apparently conflicting, reports of MUC1 expression in women.
Several monoclonal antibodies raised against the MUC1 core
protein recognize similar epitopes within a sequence
Pro-Asp-Thr-Arg-Pro in the tandem repeats (Meseguer et al.,
1998b and references therein). Glycosylation of the threonine
within the epitope and/or adjacent threonines and serines
reduces reactivity of some of these antibodies through steric
hindrance (Aplin et al., 1998 and references therein). For
example, prior enzymatic deglycosylation increases the
binding of the monoclonal antibody HMFG-1 to MUC1 in
uterine sections (Aplin et al., 1998; DeLoia et al., 1998). While
the epitopes recognized by HMFG-1 and a related antibody
HMFG-2 differ by only one amino acid (Pro-Asp-Thr-Arg and
Asp-Thr-Arg respectively), reactivity of the latter appears not
to be affected by glycosylation (DeLoia et al., 1998; Meseguer
et al., 1998b).
The function of the changes in MUC1 ‘glycoforms’ at the
uterine luminal surface is not clear. Modification with keratan
sulphate would be expected to further enhance anti-adhesive
function (Dou and Levine, 1995; Takahashi et al., 1996), an
undesirable property for an embryo attachment molecule.
Presuming an anti-adhesive function with regard to embryo
attachment in humans, MUC1 would have to be locally
removed at the site of embryo attachment as occurs in rabbits
(Hoffman et al., 1998). An interesting counterproposal is that
MUC1 may actually support embryo attachment. A recent
report suggests a decrease in sulphation at the luminal surface
during the receptive phase, implying less repulsion between the
embryo and luminal epithelium (Aplin et al., 1998). This
proposal gains strength from observations that mucins can be
selectin ligands (Lasky, 1992) and the detection of sialyl-Lewis
X and A oligosaccharides in epithelial cells in receptive phase
uteri and on MUC1 expressed by human uterine epithelial cell
lines (Hey and Aplin, 1996). Furthermore, L-selectin is
expressed at early stages of preimplantation development in the
human embryo (Campbell et al., 1995). Studies in mice of
carbohydrate motifs [lacto-N-fucopentaose-I (LNF-I)]
potentially found on mucins also may support a role in embryo
attachment (Lindenberg et al., 1988). Studies focusing on the
expression of LNF-I and selectin ligands at the luminal surface
of human uterine epithelium, as well as the expression of
adhesion molecules on the surface of human blastocyst stage
embryos, will be required to resolve these issues. Studies in
mice have revealed expression of specific cell surface oligosaccharides and lectins by attachment-competent blastocysts,
as well as potential interacting molecules on the luminal surface
of the receptive uterus (for reviews see Poirier and Kimber,
1997; Ghosh and Sengupta, 1998).
In addition to MUC1, the human cervix also expresses
several other mucin genes including MUC4, 5AC, 5B, MUC6
and MUC8 (Gipson et al., 1997). In rabbits, cervical Muc1
levels do not vary more than 2- to 3-fold in response to steroid
Mammalian reproductive tract mucins
hormones, in marked contrast to the large (≥10-fold) changes
seen in the uterus (Hewetson and Chilton, 1997; Hoffman
et al., 1998). Epithelia of both tissues express steroid hormone
receptors and are strongly influenced by ovarian steroids.
Therefore, this is a clear example of the tissue specificity of
regulation of mucin expression. It is possible that steroid
hormones modify the production of signals by underlying
stroma that, in turn, regulate mucin production in the
epithelium. Both MUC1 and MUC4 are expressed by human
vaginal epithelium, although MUC4 expression is not observed
in all cells of this tissue (Gipson et al., 1997). Cycle
(hormone)-dependent alterations in the production of cervical
vaginal mucus is a well-described clinical phenomenon (Katz
et al., 1997 and references therein); however, it is not clear if
the source of the mucins in vaginal fluids is the vaginal tissue
itself, or cells from tissues in the upper reproductive tract.
Differences in mucin expression profiles along the female
reproductive tract may explain in part the consistencies of the
mucous gel in specific regions. For example, mucin
concentration and mucous gel viscosity apparently are
increased in the cervix during the ovulatory phase of the cycle
(Wolf et al., 1977). Not surprisingly, the cervix expresses many
mucins having cysteine-rich sequences that may promote
polymerization through intermolecular disulphide bonds,
thereby increasing viscosity of the mucus layer (see Table III).
Table III. Mucin expression in mammalian reproductive tract
tissues and gametesa
Tissue/gamete
Mucins detected
Ovary
Zona pellucida glycoproteins, MUC1?
Ova
Zona pellucida glycoproteins
Oviduct/Fallopian tube
MUC1, MUC9
Uterus
MUC1, MUC6, MUC8
Sialomucin complex, MAG
Cervix
MUC1, MUC4, MUC5AC, MUC5B,
MUC6, MUC8
Vagina
MUC1, MUC4
Testis
MUC8
Spermatozoa
MUC8
Epididymis
HE6
Prostate
MUC1, MUC2
aFor
references, see text.
MAG = mouse ascites Golgi antigen.
Summary and future directions
Based on ultrastructural studies, it has been appreciated for
many years that the surfaces of mammalian reproductive tract
mucosa are covered with a thick glycocalyx; however, only
recently have mucin glycoproteins been identified at these
surfaces. In many cases, particular mucin core proteins and
289
oligosaccharide structures have been identified and changes in
the pattern of expression observed in response to hormonal
influences. Nonetheless, we still do not have a comprehensive
picture of the spectrum of mucins expressed in any
reproductive tract tissue. Furthermore, very little is known
about the regulation of mucin gene expression either by these
specific hormones or other factors. Understanding these
molecular controls over mucin expression might provide new
opportunities to modulate mucin expression in vivo. In the case
of mucin functions as a barrier to infection, it may be desirable
to develop methods to stimulate mucin expression as a
prophylactic measure. In the case of embryo implantation, it
may be desirable to develop means to reduce mucin expression
following in-vitro fertilization–embryo transfer procedures to
enhance success rates. The increasing availability of antibody
and cDNA probes to mucin glycoproteins and genes, as well as
the generation of various transgenic mice to study mucin
expression and function, will be invaluable tools in the study of
this interesting class of cell surface components.
Note added in Proof
Recently, SMC has been identified as MUC4.
References
Abdullah, K.M., Udoh, E.A., Shewen, P.E. and Mellors, A. (1992) A neutral
glycoprotease of Pasteurella haemolytica A1 specifically cleaves
O-sialoglycoproteins. Infect. Immun., 60, 56–62.
Aplin, J.D., Seif, M.W., Graham, R.A. et al. (1994) The endometrial cell
surface and implantation. Expression of the polymorphic mucin MUC-1
and adhesion molecules during the endometrial cycle. Ann. N. Y. Acad.
Sci., 734, 103–121.
Aplin, J.D., Hey, N.A. and Li, T.C. (1996) MUC1 as a cell surface and
secretory component of endometrial epithelium: reduced levels in
recurrent miscarriage. Am. J. Reprod. Immunol., 35, 261–266.
Aplin, J.D., Hey, N.A. and Graham, R.A. (1998) Human endometrial MUC1
carries keratan sulfate: characteristic glycoforms in luminal epithelium
at receptivity. Glycobiology, 8, 269–276.
Arias, E B., Verhage, H.G. and Jaffe, R.C. (1994) Complementary
deoxyribonucleic acid cloning and molecular characterization of an
estrogen-dependent human oviductal glycoprotein. Biol. Reprod., 51,
685–694.
Bobek, L.A., Tsai, H., Biesbrock, A.R. and Levine, M.J. (1993) 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.
Boshell, M., Lalani, E.N., Pemberton, L. et al. (1992) 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., 185, 1–8.
Bowen, J.A., Bazer, F.W. and Burghardt, R.C. (1996) Spatial and temporal
analyses of integrin and Muc-1 expression in porcine uterine epithelium
and trophectoderm in vivo. Biol. Reprod., 55, 1098–1106.
Campbell, S., Swann, H.R., Seif, M.W. et al. (1995) Cell adhesion molecules
on the oocyte and preimplantation human embryo. Hum. Reprod., 10,
1571–1578.
Carraway, K.L. and Hull, S.R. (1991) Cell surface mucin-type glycoproteins
and mucin-like domains. Glycobiology, 1, 131–138.
290
E.Lagow, M.M.DeSouza and D.D.Carson
Carson, D.D., Tang, J.P., Julian, J. and Glasser, S.R. (1988) Vectorial
secretion of proteoglycans by polarized rat uterine epithelial cells.
J. Cell Biol., 107, 2425–2435.
Carson, D.D., Farrar, J.D., Laidlaw, J. and Wright, D.A. (1990) Selective
activation of the N-glycosylation apparatus in uteri by estrogen.
J. Biol. Chem., 265, 2947–2955.
Cohen, M.S., Black, J.R., Proctor, R.A. and Sparling, P.F. (1984) Host
defenses and the vaginal mucosa. Scand. J. Urol. Nephrol., 86, 13–22.
D’Cruz, O.J., Wild, R.A., Medders, D.E. et al. (1993) Antigenic similarities
between respiratory and reproductive tract mucins: heterogeneity of
mucin expression by human endocervix and endometrium.
Fertil. Steril., 60, 1011–1019.
D’Cruz, O.J., Dunn, T.S., Pichan, P. et al. (1996) Antigenic cross-reactivity
of human tracheal mucin with human sperm and trophoblasts correlates
with the expression of mucin 8 gene messenger ribonucleic acid in
reproductive tract tissues. Fertil. Steril., 66, 316–326.
Debailleul, V., Laine, A., Huet, G. et al. (1998) 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.
DeLoia, J.A., Krasnow, J.S., Brekosky, J. et al. (1998) Regional
specialization of the cell membrane-associated, polymorphic mucin
(MUC1) in human uterine epithelia. Hum. Reprod., 13, 2902–2909.
DeSouza, M., Surveyor, G.S., Julian, J. et al. (1999) Muc-1: a critical
barrier in the female reproductive tract. J. Reprod. Immunol., in press.
Desseyn, J.-L., Guyonnet-Duperat, V., Porchet, N. et al. (1997a) Human
mucin gene MUC5B, the 10.7-kb large central exon encodes various
alternate subdomains resulting in a super-repeat. J. Biol. Chem., 272,
16873–16883.
Desseyn, J.-L., Aubert, J.P., Van Seuningen, I. et al. (1997b) Genomic
organization of the 3′ region of the human mucin gene MUC5B.
J. Biol. Chem., 272, 3168–3178.
Devine, P.L. and McKenzie, I.F.C. (1992) Mucins: structure, function and
association with malignancy. BioEssays, 14, 619–625.
Dohi, D.F., Sutton, R.C., Frazier, M.L. et al. (1993) Regulation of
sialomucin production in colon carcinoma cells. J. Biol. Chem., 268,
10133–10138.
Dou, C.L. and Levine, J.M. (1995) Differential effects of
glycosaminoglycans on neurite growth on laminin and L1 substrates.
J. Neurosci., 15, 8053–8066.
Draper, D.L., Donegan, E.A., James, J.F. et al. (1980) Scanning electron
microscopy of attachment of Neisseria gonorrhoeae colony phenotypes
to surfaces of human genital epithelia. Am. J. Obstet. Gynecol., 138,
818–826.
Durrant, L.G., Jacobs, E. and Price, M.R. (1994) Production of monoclonal
antibodies recognising the peptide core of MUC2 intestinal mucin.
Eur. J. Cancer, 30A, 355–363.
Erickson, A.K., Willgohs, J.A., McFarland, S.Y. et al. (1992) Identification
of two porcine brush border glycoproteins that bind to K88ac adhesion
of Escherichia coli and correlation of these glycoproteins with the
adhesive phenotype. Infect. Immun., 60, 983–988.
Eriksen, G.V., Carlstedt, I., Uldbjerg, N. and Ernst, E. (1998) Cervical
mucins affect the motility of human spermatozoa in vitro. Fertil. Steril.,
70, 350–354.
Forestner, G. (1995) Signal transduction, packaging and secretion of mucins.
Annu. Rev. Physiol., 57, 585–605.
Fox, M.F., Lahbib, F., Pratt, W. et al. (1992) Regional localization of the
intestinal mucin gene MUC3 to chromosome 7q22. Ann. Hum. Genet.,
56, 281–287.
Fung, P.Y. and Longenecker, B.M. (1991) Specific immunosuppressive
activity of epiglycanin, a mucin-like glycoprotein secreted by a murine
mammary adenocarcinoma (TA3-HA). Cancer Res., 51, 1170–1176.
Gal, R., Koren, R., Nofech-Mozes, S. et al. (1996) Evaluation of mucinous
metaplasia of the prostate gland by mucin histochemistry. Br. J. Urol.,
77, 113–117.
Gendler, S.J. and Spicer, A.P. (1995) Epithelial mucin genes.
Annu. Rev. Physiol., 57, 607–634.
Gendler, S.J., Spicer, A.P., Lalani, E.N. et al. (1991) Structure and biology of
a carcinoma-associated mucin, MUC1. Am. Rev. Respir. Dis., 144,
S42–S47.
Ghosh, D. and Sengupta, J. (1998) Molecular mechanism of embryoendometrial adhesion in primates: a future task for implantation
biologists. Mol. Hum. Reprod., 4, 733–738.
Gimmi, C.D., Morrison, B.W., Mainprice, B.A. et al. (1996) Breast
cancer-associated antigen, DF3/MUC1, induces apoptosis of activated
human T cells. Nature Med., 2, 1367–1370.
Gipson, I.K. and Inatomi, T. (1997) Mucin genes expressed by the ocular
surface epithelium. Prog. Retinal Eye Res., 16, 81–98.
Gipson, I.K., Ho, S.B., Spurr-Michaud, S.J. et al. (1997) Mucin genes
expressed by human female reproductive tract epithelia. Biol. Reprod.,
56, 999–1011.
Girling, A., Bartkova, J., Gendler, S. et al. (1989) 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, 43, 1072–1076.
Gold, D.V., Lew, K., Maliniak, R. et al. (1994) Characterization of
monoclonal antibody PAM4 reactive with a pancreatic cancer mucin.
Int. J. Cancer, 57, 204–210.
Goldstein, N.S., Qian, J. and Bostwick, D.G. (1995) Mucin expression in
atypical adenomatous hyperplasia of the prostate. Hum. Pathol., 26,
887–891.
Gollub, E.D., Goswami, S., Kouba, D. and Marom, Z. (1993) Regulation of
mucin gene expression in secretory epithelial cells. Biochem. Biophys.
Res. Commun., 197, 667–673.
Gum, J.R., Byrd, J.C., Hicks, J.W. et al. (1989) Molecular cloning of human
intestinal mucin cDNAs. J. Biol. Chem., 264, 6480–6487.
Gum, J.R., Hicks, J.W., Swallow, D.M. et al. (1990) Molecular cloning of
cDNAs derived from a novel human intestinal mucin gene. Biochem.
Biophys. Res. Commun., 171, 407–415.
Gum, J.R., Hicks, J.W., Toribara, N.W. et al. (1994) Molecular cloning of
human intestinal mucin (MUC2) cDNA. J. Biol. Chem., 269,
2440–2446.
Guyonnet-Duperat, V., Andie, J.P., Debailleul, V. et al. (1995)
Characterization of the human mucin gene MUC5AC: a consensus
cysteine-rich domain for 11p15 mucin genes? Biochem. J., 305,
211–219.
Hewetson, A. and Chilton, B.S. (1997) Molecular cloning and
hormone-dependent expression of rabbit Muc1 in the cervix and uterus.
Biol. Reprod., 57, 468–477.
Hey, N.A. and Aplin, J.D. (1996) Sialyl-Lewis x and sialyl-Lewis a are
associated with MUC1 in human endometrium. Glycoconj. J., 13,
769–779.
Hey, N.A., Graham, R.A., Seif, M.W. and Aplin, J.D. (1994) The
polymorphic epithelial mucin MUC1 in human endometrium is
regulated with maximal expression in the implantation phase.
J. Clin. Endocrinol. Metab., 78, 337–342.
Hey, N.A., Li, T.C., Devine, P.L. et al. (1995) MUC1 in secretory phase
endometrium: expression in precisely dated biopsies and flushings
from normal and recurrent miscarriage patients. Hum. Reprod., 10,
2655–2662.
Hild-Petito, S., Fazleabas, A.T., Julian, J. and Carson, D.D. (1996) Muc-1
expression is differentially regulated in uterine luminal and glandular
epithelia of the baboon (Papio anubis). Biol. Reprod., 54, 939–947.
Hilkens, J., Ligtenberg, M.J., Vos, H.L. and Litvinov, S.V. (1992) Cell
membrane-associated mucins and their adhesion-modulating property.
Trends Biochem. Sci., 17, 359–363.
Ho, J.J.L., Cheng, S. and Kim, Y.S. (1995) Access to peptide regions of a
surface mucin (MUC1) is reduced by sialic acids. Biochem. Biophys.
Res. Commun., 210, 866–873.
Ho, S.B. and Kim, Y.S. (1991) Carbohydrate antigens on cancer-associated,
mucin-like molecules. Cancer Biol., 2, 389–400.
Ho, S.B., Niehans, G.A., Lyftogt, C. et al. (1993) Heterogeneity of mucin
gene expression in normal and neoplastic tissues. Cancer Res., 53,
641–651.
Hoadley,
M.E.,
Seif,
M.W.
and
Aplin,
J.D.
(1990)
Menstrual-cycle-dependent expression of keratan sulfate in human
endometrium. Biochem. J., 266, 757–763.
Hoffman, L.H., Olson, G.E., Carson, D.D. and Chilton, B.S. (1998)
Progesterone and implanting blastocysts regulate Muc1 expression in
rabbit uterine epithelium. Endocrinology, 139, 266–271.
Mammalian reproductive tract mucins
Hull, S.R., Sugarman, E.D., Spielman, J. and Carraway, K.L. (1991)
Biosynthetic maturation of an ascites tumor cell surface sialomucin.
Evidence for O-glycosylation of cell surface glycoprotein by the
addition of new oligosaccharides during recycling. J. Biol. Chem., 266,
13580–13586.
Jentoff, N. (1990) Why are proteins O-glycosylated? Trends Biochem. Sci.,
15, 291–294.
Karlsson, N.G., Herrmann, A., Karlsson, H. et al. (1997) The glycosylation
of rat intestinal Muc2 mucin varies between rat strains and the small and
large intestine. J. Biol. Chem., 272, 27015–27034.
Katz, D.F., Slade, D.A. and Nakajima, S.T. (1997) Analysis of pre-ovulatory
changes in cervical mucus hydration and sperm penetrability.
Adv. Contracept., 13, 143–151.
Keates, A.C., Nunes, D.P., Afdhal, N.H. et al. (1997) Molecular cloning of a
major human gall bladder mucin: complete C-terminal sequence and
genomic organization of MUC5B. Biochem. J., 324, 295–303.
Kemperman, H., Wijnands, Y., Wesseling, J. et al. (1994) The mucin
epiglycanin on TA3/Ha carcinoma cells prevents α6β4-mediated
adhesion to laminin and kalinin and E-cadherin-mediated cell–cell
interaction. J. Cell Biol., 127, 2071–2080.
Kliman, H.J., Feinberg, R.F., Schwartz, L.B. et al. (1995) A mucin-like
glycoprotein identified by MAG (mouse ascites golgi) antibodies.
Am. J. Pathol., 146, 166–181.
Kobata, A. and Takasaki, S. (1992) Structure and biosynthesis of cell surface
carbohydrates. In Fukuda, M. (ed.), Cell Surface Carbohydrates and
Cell Development. CRC Press, Ann Arbor, MI, pp. 1–24.
Komatsu, M., Carraway, C.A., Fregien, N.L. and Carraway, K.L. (1997)
Reversible disruption of cell–matrix and cell–cell interactions by
overexpression of sialomucin complex. J. Biol. Chem., 272,
33245–33254.
Kuan, S.-F., Byrd, J.C., Basbaum, C. and Kim, Y.S. (1989) Inhibition of
mucin glycosylation by aryl-N-acetyl-alpha-galactosaminides in human
colon cancer cells. J. Biol. Chem., 264, 19271–19277.
Lamblin, G. and Roussel, P. (1993) Airway mucins and their role in defense
against micro-organisms. Respir. Med., 87, 421–426.
Lancaster, C.A., Peat, N., Duhig, T. et al. (1990) Structure and expression of
the human polymorphic epithelial mucin gene: an expressed VNTR
unit. Biochem. Biophys. Res. Commun., 173, 1019–1029.
Lapensee, L., Paquette, Y. and Bleau, G. (1997) Allelic polymorphism and
chromosomal localization of the human oviductin gene (MUC9).
Fertil. Steril., 68, 702–708.
Lasky, L.A. (1992) Selectins: interpreters of cell-specific carbohydrate
information during inflammation. Science, 258, 964–969.
Lesuffleur, T., Roche, F., Hill, A.S. et al. (1995) Characterization of a mucin
cDNA clone isolated from HT-29 mucus-secreting cells. J. Biol. Chem.,
270, 13665–13673.
Ligtenberg, M.J., Buijs, F., Vos, H.L. and Hilkens, J. (1992) Suppression of
cellular aggregation by high levels of episialin. Cancer Res., 52,
2318–2324.
Lindenberg, S., Sundberg, K., Kimber, S.J. and Lundblad, A. (1988) The
milk oligosaccharide, lacto-N-fucopentaose I, inhibits attachment of
mouse blastocysts on endometrial monolayers. J. Reprod. Fertil., 83,
149–158.
Linsley, P.S., Kallestad, J.C. and Horn, D. (1988) Biosynthesis of high
molecular weight breast cancer associated mucin glycoproteins.
J. Biol. Chem., 263, 8390–8397.
Litvinov, S.V. and Hilkens, J. (1993) The epithelial sialomucin, episialin, is
sialylated during recycling. J. Biol. Chem., 268, 21364–21371.
Maharajan, P. and Maharajan, V. (1986) Behavioural pattern of tumour cells
in mouse uterus. Gynecol. Obstet. Invest., 21, 32–39.
Malette, B., Paquette, Y. and Bleau G. (1995) Oviductins possess chitinaseand mucin-like domains: a lead in the search for the biological function
of these oviduct-specific ZP-associating glycoproteins. Mol. Reprod.
Dev., 41, 384–397.
Mani, S.K., Carson, D.D. and Glasser, S.R. (1992) Steroid hormones
differentially modulate glycoconjugate synthesis and vectorial secretion
by polarized uterine epithelial cells cultured in vitro. Endocrinology,
130, 240–248.
McDonald, N.Q. and Hendrickson, W.A. (1993) A structural superfamily of
growth factors containing a cystine knot motif. Cell, 73, 421–424.
291
McNeer, R.R., Carraway, C.A., Fregien, N.L. and Carraway, K.L. (1998)
Characterization of the expression and steroid hormone control of
sialomucin complex in the rat uterus: implications for uterine
receptivity. J. Cell. Physiol., 176, 110–119.
Meerzaman, D., Charles, P., Daskal, E. et al. (1994) Cloning and analysis of
cDNA encoding a major airway glycoprotein, human tracheobronchial
mucin (MUC5). J. Biol. Chem., 269, 12932–12939.
Meitinger, T., Meindl, A., Bork, P. et al. (1993) Molecular modelling of the
Norrie disease protein predicts a cystine knot growth factor tertiary
structure. Nature Genet., 5, 376–380.
Meseguer, M., Gaitan, P., Mercader, A. et al. (1998a) Hormonal regulation
in vivo of MUC1 in mock cycles from patients undergoing ovocyte
donation. Hum. Reprod., 13 (Abstract bk. 1), 121–122.
Meseguer, M., Pellicer, A. and Simon, C. (1998b) MUC1 and endometrial
receptivity. Mol. Hum. Reprod., 4, 1089–1098.
Moghissi, K.S. (1972) The function of the cervix in fertility. Fertil. Steril.,
23, 295–306.
Müller, S., Goletz, S., Packer, N. et al. (1997) Localization of
O-glycosylation
sites
on
glycopeptide
fragments
from
lactation-associated MUC1. J. Biol. Chem., 272, 24780–24793.
Muramatsu, T. (1988) Developmentally regulated expression of cell surface
carbohydrates during mouse embryogenesis. J. Cell. Biochem., 36,
1–14.
Nielsen, P.A., Bennett, E.P., Wandall, H.H. et al. (1997) Identification of a
major human high molecular weight salivary mucin (MG1) as
tracheobronchial mucin MUC5B. Glycobiology, 7, 413–419.
Nishimori, I., Perini, F., Mountjoy, K.P. et al. (1994) N-Acetylgalactosamine
glycosylation of MUC1 tandem repeat peptides by pancreatic tumor cell
extracts. Cancer Res., 54, 3738–3744.
Nollet, S., Moniaux, N., Maury, J. et al. (1998) Human mucin gene MUC4:
organization of its 5’ region and polymorphism of its central tandem
repeat array. Biochem. J., 332, 739–748.
O’Connell, B., Tabak, L.A. and Ramasubbu, N. (1991) The influence of
flanking sequences on O-glycosylation. Biochem. Biophys. Res.
Commun., 180, 1024–1030.
Ogata, S., Maimonis, P.J. and Itkowitz, S.H. (1992) Mucins bearing the
cancer-associated Sialosyl-Tn antigen mediate inhibition of natural
killer cell cytotoxicity. Cancer Res., 52, 4741–4746.
Osterhoff, C., Ivelland, R. and Kirchhoff, C. (1997) Cloning of a human
epididymis-specific mRNA, HE6, encoding a novel member of the
seven transmembrane-domain receptor superfamily. DNA Cell Biol.,
16, 379–389.
Parr, M.B. and Parr, E.L. (1986) Effects of oestradiol-17 beta and
progesterone on the number of plasma cells in uteri of ovariectomized
mice. J. Reprod. Fertil., 77, 91–97.
Pemberton, L.F., Rughetti, A., Taylor-Papadimitriou, J. and Gendler, S.J.
(1996) The epithelial mucin MUC1 contains at least two discrete signals
specifying membrane localization in cells. J. Biol. Chem., 271,
2332–2340.
Pimental, R.A., Julina, J., Gendler, S.J. and Carson, D.D. (1996) Synthesis
and intracellular trafficking of Muc-1 and mucins by polarized mouse
uterine epithelial cells. J. Biol. Chem., 271, 28128–28137.
Poirier, F. and Kimber, S. (1997) Cell surface carbohydrates and lectins in
early development. Mol. Hum. Reprod., 3, 907–918.
Porchet, N., Nguyen, V.C., Dufosse, J. et al. (1991) Molecular cloning and
chromosomal localization of a novel human tracheo-bronchial mucin
cDNA containing tandemly repeated sequences of 48 base pairs.
Biochem. Biophys. Res. Commun., 175, 414–422.
Porchet, N., Pigny, P., Buisine, M.P. et al. (1995) Human mucin genes:
genomic organization and expression of MUC4, MUC5AC and
MUC5B. Biochem. Soc. Trans., 23, 800–805.
Rose, M.C., Kaufman, B. and Martin, B.M. (1989) Proteolytic
fragmentation and peptide mapping of human carboxyamidomethylated tracheobronchial mucin. J. Biol. Chem., 264, 8193–8199.
Rossi, E.A., McNeer, R.R., Price-Schiavi, S.A. et al. (1996) Sialomucin
complex, a heterodimeric glycoprotein complex. J. Biol. Chem., 271,
33476–33485.
Roth, J., Wang,Y., Eckhardt, A.E. et al. (1994) Subcellular localization of
the UDP-N- acetyl-D-galactosamine: polypeptide N-acetylgalacto-
292
E.Lagow, M.M.DeSouza and D.D.Carson
saminyltransferase-mediated O-glycosylation reaction in the
submaxillary gland. Proc. Natl Acad. Sci. USA, 91, 8935–8939.
Rye, P.D., Bell, S.C. and Walker, R.A. (1993) Immunohistochemical
expression of tumour-associated glycoprotein and polymorphic
epithelial mucin in the human endometrium during the menstrual cycle.
J. Reprod. Fertil., 97, 551–556.
Scharfman, A., Van Brussel, E., Houdret, N. et al. (1996) Interactions
between glycoconjugates from human respiratory airways and
Pseudomonas aeruginosa. Am. J. Respir. Crit. Care Med., 154,
S163–S169.
Schlessinger, M. (1962) Uterus of rodents as site for manifestation of
transplantation immunity against transplantable tumors. J. Natl Cancer
Inst., 56, 221–234.
Schroten, H., Plogmann, R., Hanisch, F.G. et al. (1993) Inhibition of
adhesion of S-fimbriated E. coli to buccal epithelial cells by human skim
milk is predominantly mediated by mucins and depends on the period of
lactation. Acta Paediatr., 82, 6–11.
Sentinelli, S. (1993) Mucins in prostatic intra-epithelial neoplasia and
prostatic carcinoma. Histopathology, 22, 271–274.
Seregni, E., Botti, C., Massaron, S. et al. (1997) Structure, function, and gene
expression of epithelial mucins. Tumori, 83, 625–632.
Shankar, V., Pichan, P., Eddy, R.L., Jr et al. (1997) Chromosomal
localization of a human mucin gene (MUC8) and cloning of the cDNA
corresponding to the carboxy terminus. Am. J. Respir. Cell. Mol. Biol.,
16, 232–241.
Sheng, Z., Wu, K., Carraway, K.L. and Fregien, N. (1992) Molecular cloning
of the transmembrane component of the 13762 mammary
adenocarcinoma sialomucin complex. J. Biol. Chem., 267,
16341–16346.
Sherblom, A.P. and Moody, C.E. (1986) Cell surface sialomucin and
resistance to natural cell-mediated cytotoxicity of rat mammary tumor
ascites cells. Cancer Res., 46, 4543–4546.
Slomiany, B.L., Murty, V.L. and Slomiany A. (1993) Structural features of
carbohydrate chains in human salivary mucins. Int. J. Biochem., 25,
259–265.
Slomiany B.L., Murty, V.L., Piotrowski, J. and Slomiany, A. (1996) Salivary
mucins in oral mucosal defense. Gen. Pharmacol., 27, 761–771.
Surveyor, G.A., Gendler, S.J., Pemberton, L. et al. (1995) Expression and
steroid hormonal control of Muc-1 in the mouse uterus. Endocrinology,
136, 3639–3647.
Suzuki, K.Y., Sendai, Y., Onuma, T. et al. (1995) Molecular characterization
of a hamster oviduct-specific glycoprotein. Biol. Reprod., 53, 345–354.
Takahashi, K., Stamenkovic, I., Cutler, M. et al. (1996) Keratan sulfate
modification of CD44 modulates adhesion to hyaluronate.
J. Biol. Chem., 271, 9490–9496.
Tashiro, Y., Yonezawa, S., Kim, Y.S. and Sato, E. (1994) Immunohistochemical study of mucin carbohydrates and core proteins in human
ovarian tumors. Hum. Pathol., 25, 364–372.
Toribara, N.W., Roberton, A.M., Ho, S.B. et al. (1993) Human gastric
mucin. J. Biol. Chem., 268, 5879–5885.
Toribara, N.W., Ho, S.B., Gum, E. et al. (1997) The carboxyl-terminal
sequence of the human secretory mucin, MUC6. J. Biol. Chem., 272,
16398–16403.
Trivier, D., Houdret, N., Courcol, R.J. et al. (1997) The binding of surface
proteins from Staphylococcus aureus to human bronchial mucins.
Eur. Respir. J., 10, 804–810.
Troxler, R.F., Offner, G.D., Zhang, F. et al. (1995) Molecular cloning of a
novel high molecular weight mucin (MG1) from human sublingual
gland. Biochem. Biophys. Res. Commun., 217, 1112–1119.
Valdizan, M.C., Julian, J. and Carson, D.D. (1992) WGA-binding, mucin
glycoproteins protect the apical cell surface of mouse uterine epithelial
cells. J. Cell. Physiol., 151, 451–465.
van de Wiel-van Kemenade, E., Ligtenberg, M.J., de Boer, A.J. et al. (1993)
Episialin (MUC1) inhibits cytotoxic lymphocyte-target cell interaction.
J. Immunol., 151, 767–776.
Van Klinken, B.J., Dekker, J., Buller, H.A. and Einerhand, A.W. (1995)
Mucin gene structure and expression: protection vs. adhesion.
Am. J. Physiol., 269, G613–G627.
Van Klinken, B.J., Van Dijken, T.C., Oussoren, E. et al. (1997) Molecular
cloning of human MUC3 cDNA reveals a novel 59 amino acid tandem
repeat region. Biochem. Biophys. Res. Commun., 238, 143–148.
Veerman, E.C., Bank, C.M., Namavar, F. et al. (1997) Sulfated glycans on
oral mucin as receptors for Helicobacter pylori. Glycobiology, 7,
737–743.
Venegas, M.F., Navas, E.L., Gaffney, R.A. et al. (1995) Binding of type
I-piliated Escherichia coli to vaginal mucus. Infect. Immun., 63,
416–422.
Wandall, H.H., Hassan, H., Mirgorodskaya, E. et al. (1997) Substrate
specificities of three members of the human UDP-N-Acetyl-β-Dgalactosamine: polypeptide N-Acetylgalactosaminyltransferase family,
GalNAc-T1, -T2, and -T3. J. Biol. Chem., 272, 23503–23514.
Wang, Y., Agrwal, N., Eckhardt, A.E. et al. (1992) The acceptor substrate
specificity of porcine submaxillary UDP-GalNAc: polypeptide
N-Acetylgalactosaminyltransferase is dependent on the amino acid
sequences adjacent to serine and threonine residues. J. Biol. Chem., 268,
22979–22983.
Wassarman P.M. (1995) Towards molecular mechanism for gamete
adhesion and fusion during mammalian fertilization. Curr. Opin. Cell
Biol., 7, 658–664.
Wassarman, P.M. and Litscher, E.S. (1995) Sperm-egg recognition in
mammals. Curr. Top. Dev. Biol., 30, 1–19.
Wesseling, J., Van der Valk, S.W., Vos, H.L. et al. (1995) Episialin (MUC1)
overexpression inhibits integrin-mediated cell adhesion to extracellular
matrix components. J. Cell Biol., 129, 255–265.
Wesseling, J.S., vanderValk, W. and Hilkens, J. (1996) A mechanism for
inhibition of E-cadherin-mediated cell–cell adhesion by the membrane
associated mucin episialin/MUC-1. Mol. Biol. Cell, 7, 565–577.
Williams, C.J., Wreschner, D.H., Tanaka, A. et al. (1990) Multiple protein
forms of the human breast tumor-associated epithelial membrane
antigen (EMA) are generated by alternative splicing and induced by
hormonal stimulation. Biochem. Biophys. Res. Commun., 170,
1331–1338.
Wolf, D.P., Blasco, L., Khan, M.A. and Litt, M. (1977) Human cervical
mucus II. Changes in viscoelasticity during the ovulatory menstrual
cycle. Fertil. Steril., 28, 47–52.
Wu, K., Fregien, N. and Carraway, K.L. (1994) Molecular cloning and
sequencing of the mucin subunit of a heterodimeric, bifunctional cell
surface glycoprotein complex of ascites rat mammary adenocarcinoma
cells. J. Biol. Chem., 269, 11950–11955.
Yan, P.S., Ho, S.B., Itzkowitz, S.H. et al. (1990) Expression of native and
deglycosylated colon cancer mucin antigens in normal and malignant
epithelial tissues. Lab. Invest., 63, 698–706.
Yao, L., Berman, J.W., Factor, S.M. and Lowy, F.D. (1997) Correlation of
histopathologic and bacteriologic changes with cytokine expression in
an experimental murine model of bacteremic Staphylococcus aureus
infection. Infect. Immun., 65, 3889–3895.
Yazawa, S., Abbas, S.A., Madiyalakan, R. et al. (1986) N-acetylbeta-D-glucosaminyltransferases related to the synthesis of mucin-type
glycoproteins in human ovarian tissue. Carbohydr. Res., 149, 241–252.
Zhang, K., Baeckstrom, D., Brevinge, H. and Hansson, G.C. (1996) Secreted
MUC1 mucins lacking their cytoplasmic part and carrying sialyl-Lewis
a and x epitopes from a tumor cell line and sera of colon carcinoma
patients can inhibit HL-60 leukocyte adhesion to E-selectin-expressing
endothelial cells. J. Cell. Biochem., 60, 538–549.
Zrihan-Licht, S., Baruch, A., Elroy-Stein, O. et al. (1994) Tyrosine
phosphorylation of the MUC1 breast cancer membrane protein cytokine
receptor-like molecule. FEBS Lett., 356, 130–136.
Received on July 20, 1998; accepted on April 12, 1999