Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2001-12-20
2004-04-06
Lacourciere, Karen (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S325000, C435S091100, C435S091300, C536S023100, C536S023200, C536S024500, C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06716627
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of mucin 1, transmembrane. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding mucin 1, transmembrane. Such compounds have been shown to modulate the expression of mucin 1, transmembrane.
BACKGROUND OF THE INVENTION
Mucins are high-molecular-weight, heavily glycosylated proteins found in milk, mammary gland and lactating tissue, as well as other simple secretory epithelial tissues. Mucins are constituents of the physical and biological barrier in protective mucous of respiratory, ductal and glandular epithelia. In humans, at least 10 distinct epithelial mucin core polypeptide genes have been identified (MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, and MUC9), and these mucins share the common features of bearing tandem repeat domains rich in proline, serine and threonine residues and forming O-glycans, with N-acetylgalactosamine linkages at hundreds of sites. Mucins are purported to be the most polymorphic of all biological macromolecules produced by eukaryotic organisms (even more so than immunoglobulin and T cell receptors). Mucin O-glycans serve as epitopes representing blood group and as related genetically polymorphic antigens (Irimura et al.,
J. Biochem.
(
Tokyo
), 1999, 126, 975-985).
The highly-glycosylated mucin-type glycoproteins present in human urine and several normal and malignant tissues of epithelial origin are very antigenic, and in searches for epithelial and tumor-associated antigens, a large number of monoclonal antibodies have been produced which bind to the mucins. These antibodies have been used in cancer diagnosis and therapy, as well as to study the expression and variation of the PUM (peanut lectin binding urinary mucins) antigens and to confirm that the PUM locus, a highly-polymorphic “minisatellite” region of the genome, encodes a mammary mucin (Karlsson et al.,
Ann. Hum. Genet.,
1983, 47, 263-269; Swallow et al.,
Nature,
1987, 328, 82-84). A full-length cDNA encoding mucin 1, transmembrane (also known as MUC1, episialin, epitectin, polymorphic epithelial mucin, PEM, peanut-reactive urinary mucin, PUM, epithelial membrane antigen, EMA, PAS-0, NCRC11, H23 antigen, H23-ETA transmembrane antigen, DF3 antigen, and CD227) was deduced from overlapping clones isolated from a cDNA library constructed from the BT20 breast cancer cell line. The mucin 1, transmembrane gene encodes a protein with three distinct regions: a signal peptide and degenerate tandem repeats at the N-terminus; the major portion of the protein comprising 60-base pair repeats which form a variable number tandem repeats (VNTR) region, length varying with the individual; and a C-terminus comprising degenerate tandem repeats, a unique transmembrane sequence and a cytoplasmic tail (Gendler et al.,
J. Biol. Chem.,
1990, 265, 15286-15293). This VNTR region is expressed, and it accounts for the polymorphism observed in both the mucin 1, transmembrane gene and its protein product.
Concurrently, a monospecific polyclonal antiserum against deglycosylated human pancreatic tumor mucin was used to clone a mucin cDNA from an expression library prepared from the HPAF pancreatic tumor cell line (Lan et al.,
J. Biol. Chem.,
1990, 265, 15294-15299). This cDNA was found to be distinct from intestinal mucin, but to be 99% homologous to the human breast mucin CDNA cloned by Gendler, et al., leading to the suggestion that, although the native forms of the pancreatic and breast mucin proteins are distinct in size and degree of glycosylation, factors other than its primary sequence determine these characteristics, and the core protein (referred to as apomucin by Lan et al.) is encoded by same gene, hereafter referred to as mucin 1, transmembrane. Northern analyses of RNA from pancreatic and breast adenocarcinoma and colon tumor cell lines revealed a 4.4-kilobase (kb) mucin 1, transmembrane mRNA in 5 of 7 pancreatic tumor cell lines and two of two breast tumor cell lines, whereas no transcript was detected in the mucin-producing colon tumor lines tested. In addition to the 4.4 kb transcript, a larger mRNA with heterogeneous sizes greater than 7 kb was observed in the Colo 357 pancreatic cell line (Lan et al.,
J. Biol. Chem.,
1990, 265, 15294-15299).
A series of human-rodent somatic cell hybrids were used to map the PUM locus to human chromosome 1, and by in situ hybridization, the mucin 1, transmembrane gene was more finely mapped to the 1q21-24 region (Swallow et al.,
Ann. Hum.Genet.,
1987, 51, 289-294). The gene coding for Duffy blood group FY is closely linked to this same region (Swallow et al.,
Ann. Hum. Genet.,
1988, 52, 269-271) and close linkage of mucin 1, transmembrane to alpha-spectrin, a major component of the erythrocyte membrane, confirms the position of mucin 1, transmembrane at chromosomal locus 1q21 (Middleton-Price et al.,
Ann. Hum. Genet.,
1988, 52, 273-278).
The extracellular variable tandem repeat domain of mucin 1, transmembrane protein is highly O-glycosylated, with each 20 amino acid repeat bearing five potential glycosylation sites. Aberrant glycosylation has been described in malignancies. Due to the VNTRs, abberant glycosylation, and alternative splicing, a considerable number of mucin 1, transmembrane isoforms have been described. To date, these are: MUC1, the so-called “normal” isoform; MUC1/REP, expressed in cervical cancer; MUC1/A, the “cancer-specific” isoform found in thyroid carcinoma tissue; MUC1/SEC, lacking the transmembrane domain and is a secreted isoform; MUC1/X, MUC1/Y, and MUC1/Z which lack the VNTR region; and two recently identified splice variants, MUC1/C, MUC1/D, expressed in cervical carcinoma (Obermair et al.,
Gynecol. Oncol.,
2001, 83, 343-347).
In contrast to other mucins such as those secreted by goblet cells of the inner lining of the intestine, airway, and reproductive tract, mucin 1, transmembrane is an integral plasma membrane protein localized to the apical surface of polarized epithelial cells, including, but not limited to, the uterus, cervix, and vagina, as well as secretory epithelial cells of the mammary gland (Mather et al.,
Cell Tissue Res.,
2001, 304, 91-101), and to both normal and malignant lung epithelial cells (Griffiths et al.,
Dis. Markers,
1988, 6, 195-202).
The cytoplasmic tail of mucin 1, transmembrane protein is believed to interact with actin filaments of the cytoskeleton, and its relatively large, highly glycosylated extracellular domain may present a physical barrier that protects the cell with anti-invasion characteristics. Mucin 1, transmembrane may help to frustrate infection in the mammary gland (mastitis) and possibly in other sites in the body (such as bladder and kidney infections) by competitively inhibiting the binding of microorganisms. A mucin 1, transmembrane null mouse has been generated, and these knockout mice are predisposed to bacterial conjunctivitis and blepharitis, demonstrating an important role for mucin 1, transmembrane in ocular mucosal defense (Kardon et al.,
Invest. Ophthalmol. Vis. Sci.,
1999, 40, 1328-1335).
Mucin 1, transmembrane may also play a role the immune response, intracellular signaling, and in suppression of cell adhesion or wall-to-wall adherence in lumens and ducts, preventing their closure and preserving the integrity of secretory systems. Tumor cells tend to express mucin 1, transmembrane aberrantly in a non-polarized manner, potentially facilitating their tumor invasion and metastasis to other locations, and consequently, mucin 1, transmembrane may be associated with biologically aggressive tumors and a worse prognosis (Patton et al.,
Biochim. Biophys. Acta,
1995, 1241, 407-423; Rahn et al.,
Cancer,
2001, 91, 1973-1982).
The multiple functions of mucin 1, transmembrane in carcinoma-host interactions are believed to be dependent on its polymorphic nature, particularly its glycosylation status. Many carcinoma-associated markers are glycoproteins whose expression und
ISIS Pharmaceuticals Inc.
Lacourciere Karen
Licata & Tyrrell P.C.
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