Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-04-17
2002-11-19
Yucel, Remy (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023400, C536S024100, C435S070100, C435S252100, C435S252300, C435S320100, C530S350000
Reexamination Certificate
active
06482936
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of secreted proteins that are related to the nodal-related secreted subfamily, recombinant DNA molecules, and protein production. The present invention specifically provides novel peptides and proteins that effect protein phosphorylation and nucleic acid molecules encoding such peptide and protein molecules, all of which are useful in the development of human therapeutics and diagnostic compositions and methods.
BACKGROUND OF THE INVENTION
Secreted Proteins
Many human proteins serve as pharmaceutically active compounds. Several classes of human proteins that serve as such active compounds include hormones, cytokines, cell growth factors, and cell differentiation factors. Most proteins that can be used as a pharmaceutically active compound fall within the family of secreted proteins. It is, therefore, important in developing new pharmaceutical compounds to identify secreted proteins that can be tested for activity in a variety of animal models. The present invention advances the state of the art by providing many novel human secreted proteins.
Secreted proteins are generally produced within cells at rough endoplasmic reticulum, are then exported to the golgi complex, and then move to secretory vesicles or granules, where they are secreted to the exterior of the cell via exocytosis.
Secreted proteins are particularly useful as diagnostic markers. Many secreted proteins are found, and can easily be measured, in serum. For example, a ‘signal sequence trap’ technique can often be utilized because many secreted proteins, such as certain secretory breast cancer proteins, contain a molecular signal sequence for cellular export. Additionally, antibodies against particular secreted serum proteins can serve as potential diagnostic agents, such as for diagnosing cancer.
Secreted proteins play a critical role in a wide array of important biological processes in humans and have numerous utilities; several illustrative examples are discussed herein. For example, fibroblast secreted proteins participate in extracellular matrix formation. Extracellular matrix affects growth factor action, cell adhesion, and cell growth. Structural and quantitative characteristics of fibroblast secreted proteins are modified during the course of cellular aging and such aging related modifications may lead to increased inhibition of cell adhesion, inhibited cell stimulation by growth factors, and inhibited cell proliferative ability (Eleftheriou et al.,
Mutat Res
1991 Mar-Nov;256(2-6): 127-38).
The secreted form of amyloid beta/A4 protein precursor (APP) functions as a growth and/or differentiation factor. The secreted form of APP can stimulate neurite extension of cultured neuroblastoma cells, presumably through binding to a cell surface receptor and thereby triggering intracellular transduction mechanisms. (Roch et al.,
Ann NY Acad Sci
1993 Sep. 24;695:149-57). Secreted APPs modulate neuronal excitability, counteract effects of glutamate on growth cone behaviors, and increase synaptic complexity. The prominent effects of secreted APPs on synaptogenesis and neuronal survival suggest that secreted APPs play a major role in the process of natural cell death and, furthermore, may play a role in the development of a wide variety of neurological disorders, such as stroke, epilepsy, and Alzheimer's disease (Mattson et al.,
Perspect Dev Neurobiol
1998; 5(4):337-52).
Breast cancer cells secrete a 52 K estrogen-regulated protein (see Rochefort et al.,
Ann N Y Acad Sci
1986;464:190-201). This secreted protein is therefore useful in breast cancer diagnosis.
Two secreted proteins released by platelets, platelet factor 4 (PF4) and beta-thromboglobulin (betaTG), are accurate indicators of platelet involvement in hemostasis and thrombosis and assays that measure these secreted proteins are useful for studying the pathogenesis and course of thromboembolic disorders (Kaplan,
Adv Exp Med Biol
1978;102:105-19).
Vascular endothelial growth factor (VEGF) is another example of a naturally secreted protein. VEGF binds to cell-surface heparan sulfates, is generated by hypoxic endothelial cells, reduces apoptosis, and binds to high-affinity receptors that are up-regulated by hypoxia (Asahara et al.,
Semin Interv Cardiol
1996 Sep; 1 (3):225-32).
Many critical components of the immune system are secreted proteins, such as antibodies, and many important functions of the immune system are dependent upon the action of secreted proteins. For example, Saxon et al.,
Biochem Soc Trans
1997 May;25(2):383-7, discusses secreted IgE proteins.
For a further review of secreted proteins, see Nilsen-Hamilton et al.,
Cell Biol Int Rep
1982 Sep;6(9):815-36.
Nodal Proteins
Nodal and Nodal-related proteins have functions in mesoderm and endoderm induction and formation, as well as subsequent organization of axial structures such as heart and stomach in early embryogenesis. It has been demonstrated that dorsal tissue in a developing vertebrate embryo contributes predominantly to the axial structures of the notochord and pre-chordal plate while it recruits surrounding cells to form non-axial embryonic structures. Recent genetic and molecular studies in mouse, zebrafish and Xenopus reveal the molecular evidences of Nodal signaling (Zhou et al, Nature 361: 543-547 (1993); Feldman et al, Nature 395: 181-185, (1998); Rebagliati et al, Dev. Biol. 199: 261-272 (1998); Rebagliati MR, et al., Proc. Natl. Acad. Sci. USA. 95: 9932-9937 (1998); Sampath et al, Nature 395: 185-189 (1998); Ezal et al, J. Biol. Chem. 275: 14124-14131 (2000); Takahashi et al, Development 127: 5319-5329 (2000)). When squint and cyclops of zebrafish Nodal-related genes become simultaneously disrupted, embryos fail to form mesoderm and endoderm. Nodal-related genes Xnr5 and Xnr6 have been reported to initiate inductive events in Xenopus Nierwkoop center. Mouse Nodal gene has been identified through the insertional mutation. One mouse Nodal mutant (a retrovirally-induced recessive prenatal lethal mutation) fails to form mesoderm, and its embryonic ectoderm over-proliferates and subsequently degenerates.
The Nodal and Nodal-related proteins have been identified to use extracellular factors of transforming growth factors beta (TGF-beta) for signaling relay. Nodal signaling pathway is suggested as following (Stemple, Curr. Biol. 10: R843-846 (2000); Alexander and Stainier, Curr. Biol. 9:1147-1157 (1999) ). Nodal ligands interact with their co-factors to activate activin type I and type II or related receptors, which phosphorylate Smad2. The phosphorylated Smad2 forms a complex with Smad4 for nuclear import. In the nucleus, the Smad2/Smad4 complex serves as an effector of TGF-beta signaling by regulating transcription factors Fast-1 and Mixer, which control the expression of the genes for the development of dorsal axial structures and left-right asymmetry.
During gastrulation, the three germ layers of the embryo are formed and organized along the anterior-posterior body axis. In the mouse, gastrulation involves the delamination of ectodermal cells through the primitive streak and their differentiation into mesoderm. These processes do not occur in embryos homozygous for a retrovirally induced recessive prenatal lethal mutation, the strain 413-d insertional mutation. Instead of giving rise to mesoderm, embryonic ectoderm in 413-d mutants overproliferates and then rapidly degenerates, although extraembryonic lineages remain viable. For more information, see Dubois, et al., J Biol Chem. 1995 May 5;270(18):10618-24.
Nodal, a member of the transforming growth factor beta (TGF-beta) superfamily, is implicated in many events critical to the early vertebrate embryo, including mesoderm formation, anterior patterning, and left-right axis specification. Experimental evidence has demonstrated that nodal signaling activates pAR3-Lux, a luciferase reporter previously shown to respond specifically to activin and TGF-beta. However, nodal is unable to induce pTlx2-Lux, a reporter specifically responsive to bone morphogenetic proteins
Brandenberger Ralph
Gong Fangcheng
Higgins Maureen E.
Hu Song
Ketchum Karen A.
Genomics Celera
Karjala Justin
Pappu Sita
PE Corporation (NY)
Yucel Remy
LandOfFree
Isolated human secreted proteins, nucleic acid molecules... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Isolated human secreted proteins, nucleic acid molecules..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Isolated human secreted proteins, nucleic acid molecules... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2941765