Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-08-16
2003-02-25
Slobodyansky, Elizabeth (Department: 1652)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S069100, C435S252300, C435S320100, C435S325000, C536S023500
Reexamination Certificate
active
06524799
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to mammalian cDNAs which encode SPARC-related proteins and to the use of the cDNAs and the encoded proteins in the diagnosis and treatment of cell proliferative disorders.
BACKGROUND OF THE INVENTION
Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of molecules, biochemical and physiological mechanisms, and metabolic pathways. Despite different evolutionary pressures, the proteins of nematode, fly, rat, and man have common chemical and structural features and generally perform the same cellular function. Comparisons of the nucleic acid and protein sequences from organisms where structure and/or function are known accelerate the investigation of human sequences and allow the development of model systems for testing diagnostic and therapeutic agents for human conditions, diseases, and disorders.
The interaction of a cell with its surrounding extracellular matrix (ECM) influences cell behavior. The ECM, composed of fibrous proteins, proteoglycans and glycoproteins, fills the extracellular space with an elaborate protein network that establishes cellular shape, adhesion, detachment, motility, growth, division, and differentiation. Variations in the composition of the ECM determine the distinctive character of tissues and account for differences in strength and flexibility of connective tissues such as skin, bone, tendon, ligament and cartilage. Restructuring of the ECM accompanies embryonic development, tissue remodeling, angiogenesis, and wound healing.
Glycoproteins of the ECM typically contain multiple domains that mediate protein-protein interactions among ECM proteins and between ECM proteins and cell surface receptors. They frequently contain a variety of post-translational modifications that are required for their function, including covalently attached N- and O-linked complex-carbohydrates, phosphorylated serine and threonine residues and sulfated tyrosine residues. SPARC, an abbreviation for secreted protein acidic and rich in cysteine, also termed osteonectin, BM-40, and 43K protein, is an ECM glycoprotein that carries out multiple functions (Lane and Sage (1994) FASEB J 163-173; Motamed (1999) Int J Biochem Cell Biol 31:1363-1366). It has a molecular weight of 33 kDa in the absence of post-translational modifications, is 303 amino acids in length, and contains covalently attached N-linked complex-type carbohydrate and a signal peptide of 17 amino acids. Among its roles, SPARC modulates cell shape, adhesion, and migration of cells. Cells which over-express SPARC have a rounded morphology, whereas cells which under-express SPARC flatten. Acting as an anti-adhesin, SPARC disrupts interactions of cells with other ECM proteins. It is expressed during embryogenesis, tissue remodeling and repair. SPARC is present at high levels in developing bone and teeth, where it may be involved in calcification and calcium ion binding and may function in the development of ossified and mineralized tissues. SPARC is also present at high concentrations in activated platelets and megakaryocytes. SPARC binds cytokines, divalent cations, several collagen types, hydroxyapatite, albumin, thrombospondin and cell membranes on platelets and endothelial cells. It modulates the responses of cells to cytokines and inhibits the progression of the cell cycle from G
1
to S phase.
SPARC is made up of three domains, which individually have been shown to carry out specific functions (Motamed, supra). The acidic domain binds Ca
2+
, inhibits cell spreading and chemotactic responses to growth factors, modulates levels of plasminogen activator inhibitor-1, fibronectin, and thrombospondin-1. The cysteine-rich domain has homology with follistatin, an inhibitor of transforming growth factor b-like cytokines, and also shows similarity to serpin-type protease inhibitors and epidermal growth factor (EGF)-like motifs. This domain controls cell proliferation, angiogenesis, and disassembly of focal adhesions that link the ECM to the actin cytoskeleton. The extracellular calcium-binding domain contains an EF-hand motif, binds to cells and several types of collagen, induces matrix metalloproteinases, inhibits cell spreading and proliferation, and controls focal adhesions. Binding of collagen is dependent on Ca
2+
and the state of protein glycosylation.
During normal development, angiogenesis, and wound healing, SPARC modulates the effects of a variety of growth factors involved in cell cycle control, cell migration, and proliferation. Perturbed cellular regulation by growth factors is associated with altered levels of SPARC expression and pathological processes in various tissues. For example, SPARC shows high levels of expression in lesions of atherosclerosis compared to normal vessels (Raines et al. (1992) Proc Natl Acad Sci 89:1281-1285). It controls the activity of platelet-derived growth factor (PDGF), which promotes cell migration, proliferation, and cellular metabolic changes. SPARC binds to PDGF and inhibits its interaction with receptors. By regulating the availability of PDGF in response to vascular injury, SPARC may control proliferative repair processes. SPARC delays the entry of aortic endothelial cells into S phase and may facilitate withdrawal from the cell cycle in response to injury or developmental signals (Funk and Sage (1991) Proc Natl Acad Sci 88:2648-2652). SPARC may also play a role in the calcification of atherosclerotic plaques (Watson et al. (1994) J Clin Invest 93:2106-2113).
SPARC shows high levels of expression in brain tumor cells in gliomas where it controls the activity of vascular endothelial growth factor (VEGF), the principal angiogenic growth factor identified in human astroglial tumors (Vajkoczy et al. (2000) Int J Cancer 87:261-268). VEGF participates in a signal-transduction pathway that mediates glioma angiogenesis through stimulation of tyrosine phosphorylation and activation of mitogen-activated protein kinases. SPARC binds to VEGF and inhibits its association with cell-surface receptors. In addition, the anti-adhesive properties of SPARC and its ability to induce and activate proteolytic enzymes that degrade the ECM may also play roles in promoting cell migration and tumor cell infiltration into surrounding tissue.
Overexpression of SPARC is also associated with osteoarthritis and rheumatoid arthritis (Nakamura et al. (1996) Arthritis and Rheumatism 39:539-551). High levels of SPARC are found in cartilage and synovial fluids of patients with osteoarthritis or rheumatoid arthritis compared to levels in normal cartilage. Levels of SPARC increase in articular chondrocyte cultures in response to transforming growth factor b1 and bone morphogenetic protein 2 and decrease in response to inflammatory cytokines, IL-1b, IL-1a, tumor necrosis factor a, lipospolysaccharide, phorbol myristate acetate, basic fibroblast growth factor, and dexamethasone. SPARC activates expression of matrix metalloproteinases in synovial fibroblasts and may play roles in the destruction and repair of cartilage.
In addition, aberrant expression of SPARC is associated with a number of other diseases. SPARC shows high levels of expression in breast, ovarian and prostate cancer where it may facilitate tumor progression through control of cell adhesion, growth factors and matrix metalloproteinase activity (Gilles et al. (1998) Cancer Res 58:5529-5536; Porter et al. (1995) J Histochem Cytochem 43:791-800; Brown et al. (1999) Gynecol Oncol 75:25-33; Thomas et al. (2000) Clin Cancer Res 6:1140-1149). Elevated expression of SPARC is associated with Scleroderma (Unemori and Amento (1991) Curr Opin Rheumatol 3:953-959), human lens cataracts (Kantorow et al. (2000) Mol Vis 6:24-29) and ECM deposits in renal disease (Bassuk et al. (2000) Kidney Int 57:117-128). The discovery of mammalian cDNAs encoding SPARC-related proteins satisfies a need in the art by providing compositions which are useful in the diagnosis and treatment of c
Krasnow Randi E.
Walker Michael G.
Incyte Genomics Inc.
Incyte Genomics, Inc.
Slobodyansky Elizabeth
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