Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1999-08-12
2003-11-18
Ungar, Susan (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C536S023100, C514S002600, C424S185100
Reexamination Certificate
active
06649737
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of human galactosyltransferases and to the use of these sequences in the diagnosis, treatment, and prevention of cancer, developmental disorders, reproductive disorders, and autoimmune/inflammatory disorders.
BACKGROUND OF THE INVENTION
Epithelia, composed of sheets of highly differentiated epithelial cells, cover almost all internal and external body and organ surfaces, such as those of the intestine, kidney, pancreas, lung, mouth, and cervical tract. Epithelia regulate the exchange of substances between tissue compartments and with the outside environment. Regulated changes in embryonic epithelial cell arrangement and shape lead to the formation of internal organs. Secreted and membrane-bound proteins produced by the mesenchyme regulate these changes. It is hypothesized that regulation of cell/cell adhesion and cell motility plays an important role in epithelial morphogenesis. (Goode, S. et al. (1996) Development 122:3863-3879; Lodish, H. et al. (1995)
Molecular Cell Biology
, Scientific American Books, New York, N.Y. pp. 196-197, 623-624, 1167-1172; and Gumbiner, B. M. (1992) Cell 69:385-387.)
The follicular epithelium of the fruitfly
Drosophila melanogaster
has been used as a model system for epithelial morphogenesis. Drosophila is a useful system in which to study growth, differentiation, and tumor suppression as many of its genes have mammalian homologs. (Watson, K. L. et al. (1994) J. Cell Sci. Suppl. 18:19-33; and Lodish, supra., pp. 1167-1172.) The follicular epithelium, a monolayer of somatic cells that develops along with the germline during oogenesis, completely surrounds each developing egg chamber and eventually secretes components of the eggshell. Both the follicular epithelium and the oocyte have distinct dorsal-ventral asymmetry established by the interaction of at least 13 genes, some expressed in the follicle and some in the oocyte. Mutations in these genes lead to either dorsalization or ventralization of the eggshell and embryo. (Morisato, D. and Anderson, K. V. (1995) Annu. Rev. Genetics 29:371-399.)
Brainiac, a gene important for correct development of the follicular epithelium, may cooperate with the genes egghead and notch to mediate germline-follicle cell adhesion. Brainiac mutant females and their offspring have multiple defects including ventralization of the eggshell, gaps in the follicular epithelium, and multiple layers of follicle cells around oocytes. The described overproliferation of follicle cells is similar to adenoma tumors. Brainiac females lay fewer eggs than wild-type flies, an occurrence likely due to destruction of mutant egg chambers within the mother. The embryos produced have a cancer-like neurogenic phenotype due to the conversion of epidermal cells to neuroblasts, resulting in excess nervous tissue. The brainiac gene, present on the X chromosome, encodes a 325 to amino acid protein with a putative signal sequence. The brainiac gene is expressed constitutively in the germline during the first 12 hours of embryogenesis. (Morisato and Anderson, supra; Goode, S. et al. (1992) Development 116:177-192; Goode, S. et al. (1996) Developmental Biol. 178:35-50; and Goode, S. et al. (1996) Development, supra.)
Recent work suggests that brainiac protein is a &bgr;1,3-galactosyltransferase. (Yuan, Y. P. et al. (1997) Cell 88:9-11; and Hennet, T. et al. (1998) J. Biol. Chem. 273:58-65.) Galactosyltransferases are enzymes that transfer galactose to N-acetylglucosamine (GlcNAc)-terminating oligosaccharide chains that are part of glycoproteins or glycolipids or are free in solution. (Kolbinger, F. et al. (1998) J. Biol. Chem. 273:433-440.) &bgr;1,3-galactosyltransferases form Type I carbohydrate chains with Gal (&bgr;1-3)GlcNAc linkages. Known human and mouse &bgr;1,3-galactosyltransferases appear to have a short cytosolic domain, a single transmembrane domain, and a catalytic domain with eight conserved regions. (Kolbinger, supra; and Hennet, supra.) In mouse UDP-galactose:&bgr;-N-acetylglucosamine &bgr;1,3-galactosyltransferase-I region 1 is located at amino acid residues 78-83, region 2 is located at amino acid residues 93-102, region 3 is located at amino acid residues 116-119, region 4 is located at amino acid residues 147-158, region 5 is located at amino acid residues 172-183, region 6 is located at amino acid residues 203-206, region 7 is located at amino acid residues 236-246, and region 8 is located at amino acid residues 264-275. (Hennet, supra.) A variant of a sequence found within mouse UDP-galactose:&bgr;-N-acetylglucosamine &bgr;1,3-galactosyltransferase-I region 8 is also found in bacterial galactosyltransferases, suggesting that this sequence defines a galactosyltransferase sequence motif. (Hennet, supra.) &bgr;1,4-galactosyltransferases, which form Type II carbohydrate chains with Gal (&bgr;1-4)GlcNAc linkages, are localized to both the Golgi and the cell surface. These enzymes have a short cytosolic domain, a transmembrane domain, and stem and catalytic domains which face the Golgi lumen or cell surface. A soluble &bgr;1,4-galactosyltransferase is formed by cleaving the membrane-bound form. Amino acids conserved among &bgr;1,4-galactosyltransferases include two disulfide-bonded cysteines and a putative UDP-galactose-binding site in the catalytic domain. (Yadav, S. and Brew, K. (1990) J. Biol. Chem. 265:14163-14169; Yadav, S. P. and Brew, K. (1991) J. Biol. Chem. 266:698-703; and Shaper, N. L. et al. (1997) J. Biol. Chem. 272:31389-31399.) &bgr;1,4-galactosyltransferases have several specialized roles in addition to synthesizing carbohydrate chains on glycoproteins or glycolipids. In mammals, a &bgr;1,4-galactosyltransferase, as part of a heterodimer with &agr;-lactalbumin, functions in lactating mammary gland lactose production. A &bgr;1,4-galactosyltransferase on the surface of sperm functions as a receptor that specifically recognizes the egg. Cell surface &bgr;1,4-galactosyltransferases also function in cell adhesion, cell/basal lamina interaction, and normal and metastatic cell migration. (Shur, B. D. (1993) Curr. Opin. Cell Biol. 5:854-863; and Shaper, supra.) An aberrantly cleaved soluble &bgr;1,4-galactosyltransferase is secreted by a human ovarian cancer cell line. (Uejima, T. et al. (1992) Cancer Res. 52:6158-6163.)
Galactosyltransferases are part of a larger class of enzymes, the glycosyltransferases, which are implicated in the regulation of cellular growth, development, and differentiation. Many glycosyltransferases are localized to the Golgi while others are present on the cell surface and as soluble extracellular proteins. Cell surface membrane-bound glycosyltransferases may function in cell adhesion by binding carbohydrate substrates on adjacent cell surfaces or in the extracellular matrix. Secreted glycosyltransferases, derived in some cases from proteolytic cleavage of membrane-bound forms, may trigger cell surface receptors by binding their bound carbohydrates or may modify carbohydrates on cell surface molecules in a regulated fashion. Extracellular carbohydrate moieties are developmentally regulated and may be involved in the regulation of cell migration. (Yuan, supra; Shur, supra; and Paulson, J. C. and Colley, K. J. (1989) J. Biol. Chem. 264:17615-17618.) Glycosyltransferases may be involved in autoimmune/inflammatory disorders as many humans with autoimmune thyroid disorders have high levels of circulating antibodies directed against the enzymatic product of &agr;1,3galactosyltransferase. (Etienne-Decerf, J. et al. (1987) Acta Endocrinol. 115:67-74.)
The discovery of new human galactosyltransferases and the polynucleotides encoding them satisfies a need in the art by providing new compositions useful in the diagnosis, treatment, and prevention of cancer, developmental disorders, reproductive disorders, and autoimmune/inflammatory disorders.
SUMMARY OF THE INVENTION
The invention features substantially purified polypeptides, human galactosyltransferases, referred to collectively as “HUGA” and individually as “HUGA-1”
Corley Neil C.
Guegler Karl J.
Hillman Jennifer L.
Patterson Chandra
Shah Purvi
Davis Minh Tam
Incyte Genomics Inc.
Incyte Genomics, Inc.
Ungar Susan
LandOfFree
Human galactosyltranferases does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Human galactosyltranferases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Human galactosyltranferases will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3155237