Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-07-02
2001-05-29
Caruta, Anthony C. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S001001, C536S018700, C536S022100, C536S023100
Reexamination Certificate
active
06239266
ABSTRACT:
INTRODUCTION
BACKGROUND
Control of cellular proliferation is of great importance for many normal and abnormal biological processes; including development, wound healing, programmed cell death, angiogenesis and tumorigenesis. A myriad of components involved in the regulation of cell proliferation have been identified, including growth factors, cell cycle regulators, oncogenes and tumor suppressor genes. One of the less well-understood aspects of oncogenesis is the change in glycosylation of certain polypeptides.
The transfer of glycosyl residues from nucleotide-activated sugar molecules to other carbohydrates or to peptides is catalyzed by glycosyltransferases, whose specificity is restricted to the formation of a single glycosidic bond linking two specific sugar residues or a sugar residue to an aglycone. The cell and tissue-specific expression of glycosyltransferases depends on the differentiation, development and malignant transformation of the cell.
Aberrant glycosylationof glycosphingolipids and glycoproteins in tumor cells has been implicated as an essential mechanism in defining stage, direction, and fate of tumor progression. Clinical studies have shown a clear correlation between aberrant glycosylation status of primary tumor and invasive/metastatic potential of human cancer as reflected by 5- or 10-year survival rates of patients. Carbohydrates expressed in tumor cells may be adhesion molecules, or may modulate adhesion receptor function. Some are known to be directly involved in cell adhesion, and are recognized by selectins or other carbohydrate-binding proteins, or by complementary carbohydrates. N- or O-glycosylation of functionally important membrane components may alter tumor cell adhesion or motility in a direction that either promotes or inhibits invasion and metastasis. Examples of such receptors are E-cadherin, integrins, immunoglobulin family receptors, e.g. CD44, and lysosome-associated membrane protein.
Alternatively, gangliosides and sphingolipids may modulate transmembrane signaling essential for tumor cell growth, invasion, and metastasis. The transducer molecules susceptible to gangliosides and sphingolipids include integrin receptors, tyrosine kinase-linked growth factor receptors, protein kinase C, and G-protein-linked receptor affecting protein kinase A. Some glycosphingolipids (e.g., Gb3Cer, Le(y), ceramide, and sphingosine induce tumor cell differentiation and subsequent apoptosis. A crucial mechanism for inhibition of metastasis may involve blocking of transmembrane signaling for expression of P- and E-selectin.
One substrate for glycosyltransferases are mucins, which are heavily glycosylated high molecular weight glycoproteins. In epithelial cancers such as colorectal cancer, both qualitative and quantitative alterations in carbohydrate and polypeptide moieties of mucin glycoproteins occur. These changes in mucin glycoproteins are one of the most common phenotypic markers of colorectal carcinogenesis and may play an important pathobiological role. The increased exposure of peptide epitopes of mucin glycoproteins in colorectal cancer appears to be due to either abnormal glycosylation or altered levels of mucin gene transcription.
Alteration of cell surface carbohydrate antigens during malignant transformation is a well-known phenomenon observed in various tumors. In prostatic carcinoma, nearly total deletion of normally occurring ABO and type I-based Lewis antigens, Le(a) and Leb, has been observed in several studies. Experimental results suggest an alteration in glycosyl transferase activity in prostatic carcinoma, with preserved or increased activity of enzymes responsible for the synthesis of the type II core sequence. During the transformation of normal cells to colon carcinoma cells, there is an increase in the presence of mucin carbohydrate moieties that are not detectable in normal cells.
The identification of proteins involved with tumor growth and metastasis is of great interest for clinical and research purposes. Understanding the involvement of glycosyl transferases, and the effect of specific changes in the glycosylation of their substrates may provide new therapeutic approaches.
RELEVANT LITERATURE
The cDNA cloning and sequencing of several human UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-Acetylgalactosaminyltransferases (GALNT1, 2 and 3) have been reported, by Bennett et al. (1996)
J. Biol. Chem.
271:17006-17012; White et al. (1995)
J. Biol. Chem.
270:24156-24165; and Meurer et al. (1995)
J. Biochem.
118:568-574. A general review of the molecular and cell biology of glycosyltransferases may be found in Kleene and Berger (1993)
Biochim Biophys Act.
1154:283-325. A review of the alteration in carbohydrate moieties during malignant transformation of colon mucosa may be found in Hanski et al. (1992) Cancer Journal 5.
Loss of heterozygosity (LOH) on 3p is frequent in human renal cell carcinomas, lung cancers, and breast cancers. A detailed map of a 5 cM region on 3p24.3-25.1 flanked by D3S1286 and D3S1585, which is commonly deleted in tumors, may be found in Matsumoto et al. (1997)
Genes Chromosomes Cancer
20:268-274. A loss of heterozygosity has also been reported in human prostatic adenocarcinoma on the 3p24-26 and 3p22-12 regions of the short arm of chromosome 3 by Dahiya et al. (1997)
Int J Cancer
71(1):20-25. Deletion in this region have also been reported for human cutaneous squamous cell neoplasms (Sikkink et al. (1997)
J Invest Dermatol
109(6):801-805); in squamous cell carcinoma of the head and neck (Buchhagen et al. (1996)
Head Neck
18(6):529-537); and in transitional cell carcinoma of the urinary bladder (Li et al. (1996)
Am J Pathol
149(1):229-235).
Public human EST sequences corresponding to ZAP-3 include AA971319; AA236602; AA055179; AA055174; AA055297; and AA368180; accessible through Genbank. A mouse EST having sequence similarity may be accessed as W12343.
SUMMARY OF THE INVENTION
Isolated nucleotide compositions and sequences are provided for ZAP-3 genes. Loss of heterozygosity at the ZAP-3 locus is associated with the oncogenesis of human cancers. The ZAP-3 nucleic acid compositions find use in identifying homologous or related genes; in producing compositions that modulate the expression or function of its encoded protein, ZAP-3; for gene therapy; mapping functional regions of the protein; and in studying associated physiological pathways.
In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of cancer, identification of cell type based on expression, and the like. ZAP-3, anti-ZAP-3 antibodies and ZAP-3 nucleic acid sequences are useful as diagnostics, and to identify cancers having mutations in this gene.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
ZAP-3 gene compositions and methods for their isolation are provided.
Certain human cancers, particularly epithelial cell tumors, e.g. carcinomas of the breast, colon, cervix and lung; mesotheliomas, neuroblastomas, etc., show loss of heterozygosity of ZAP-3, indicating that the gene product functions as a tumor suppressor. The ZAP-3 sequence is consistent with a predicted function as an N-acetylgalactosaminyltransferase (GALNT) involved in protein glycosylation.
The ZAP-3 genes and fragments thereof, encoded protein, and anti-ZAP-3 antibodies are useful in characterizing the phenotype of tumors that are associated with this gene. The characterization is useful for determining further treatment of the patient. Tumors may be typed or staged as to the ZAP-3 status, e.g. by detection of mutated or deleted sequences, antibody quantitation of the protein products, and functional assays for altered ZAP-3 activity levels. Tumors associated with loss of ZAP-3 include a number of carcinomas known to have deletions in the region of chromosome 3 p 24.
CHARACTERIZATION OF ZAP-3
Comparative sequence alignments indicate that ZAP-3 is a novel N-acetylgalactosaminyltransferase. The association of ZAP-3 loss of heterozygosity (LOH) with tumors and its predicted biological activity indicate that the in
Munroe David
Pribill Ingrid
Bozicevic Field & Francis LLP
Caruta Anthony C.
Harris Alama M.
Sherwood Pamela J.
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