Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1992-09-24
1995-11-07
Scheiner, Toni R.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
436 64, 436813, 530350, 530395, 530397, 530399, 530828, G01N 33574
Patent
active
054647517
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the field of substances useful for modulating the metabolism of cells; more particularly the present invention relates to the field of proteinaceous substances useful for modulating the metabolism of cells.
BACKGROUND OF THE INVENTION
The neu gene product is a transmembrane growth-factor-receptor-like tyrosine kinase. It was originally isolated from chemically induced rat neuroblastomas that developed in the offspring of rodents exposed to ethylnitrosourea at a discrete time period of gestation. The chemically induced mutagenic event results in a point mutation (an adenine to thymidine) in the neu gene at the nucleotide level which translates into a single amino acid substitution (valine to glutamic acid) in the neu gene product's transmembrane region. The tyrosine kinase domain of the rat neu gene product becomes constitutively activated by this point mutation in its transmembrane region. The neu gene encodes a 185 Kd surface glycoprotein, termed p185, that possesses tyrosine kinase activity and is structurally similar to the epidermal growth factor receptor (EGFR) at the nucleotide and amino acid level. However, the neu gene has been shown to be distinct from the epidermal growth factor receptor-encoding gene (the c-erb-B gene) by detailed molecular analysis and chromosomal localization studies. The neu gene product's similarity with the epidermal growth factor receptor (EGFR) suggests that p185 is also a growth factor receptor of an as yet unidentified growth modulating factor. The rat and human neu genes are 90% homologous. The relative molecular masses of their protein products differ slightly, Mr=185 kDa for the rat protein and 190 kDa for the human protein. This discrepancy is thought to result from interspecies differences in post-translational modification. See Greene, M. I. et al., "Receptor Systems in Tissues of the Nervous System", Immunological Reviews, Number 100, December 1987 for a review of the neu oncogene, its product and function.
The neu gene and neu gene product refers herein to all mammalian and vertebrate homologies of this gene and its protein product. As used herein, the oncogenic form of the rat neu gene product will be denoted as p185neu. The normal cellular non-oncogenic gene product will be denoted as p185c-neu. The human homologue of the rat neu gene product is referred to herein as c-erb-B-2 or human neu. p185 written alone broadly refers herein to rat and human and other mammalian homologues of the rat neu gene product. p185 involvement in neoplasia and its growth factor receptor like attributes suggest that p185 protein plays an important role in normal and abnormal growth and differentiation of the cells in which it is expressed.
p185 has been found in variety of tissues derived from developing and adult animals in a developmental stage and tissue specific manner, Kokai, Y. et al., (1987) Proc. Natl. Acad. Sci. U.S.A. 84: 8498-8501; Maguire, H. C. et al., (1989) J. Investigative Dermatology 92: 786-790; Cohen, J. A. et al, (1989) Oncogene 4: 81-88. Expression of p185 in the adult rat and human has been detected in the epithelial layers of intestinal villi, basal layer and hair follicles of the skin, pulmonary bronchioles, proximal renal tubules, fallopian tubes, mammary ducts, bladder, and uterine endometrium and in some developing and adult peripheral and central glial cells. Neural and connective tissues express neu during a relatively narrow time window in mid to late gestation, but show no expression in the adult. In secretory epithelial layers of other organs, expression of the neu gene persists into adulthood. Lymphoid tissues do not appear to express the neu gene at any developmental stage.
p185c-neu is expressed on the surface of a number of normal cell types and on the surface of some tumors. Minimal expression of p185c-neu has been found in ependyma, choroid plexus, ciliary body, terminal bronchial epithelium, ovarian stromal epithelium and the loop of Henle. Genitourinary epithelium and normal skin app
REFERENCES:
Lupu, R., et al., Princess Takamatsu Symp., vol. 22, pp. 49-60, 1991 (Abstract Only).
Matrisian, et al., "Further Purification of Epidermal Growth Factor by High Performance Liquid Chromatography," Anal. Biochem. 125(2), pp. 339-351, 1982. Abstract only.
Drebin et al., "Down-Modulation of an Oncogene Protein Product and Reversion of the Transformed Phenotype by Monoclonal Antibodies," Cell 41:695-706, 1985.
Drebin et al., "Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule synergistic anti-tumor effects in vivo," Oncogene 2:273-277, 1988.
Yarden et al., "Experimental approaches to hypothetical hormones: Detection of a candidate ligand of the neu protooncogene," Proc. Natl. Acad. Sci. USA 86:3179-3183, 1989.
Williams et al., "Platelet-derived Growth Factor Receptors Form a High Affinity State in Membrane Preparations," J. Biol. Chem. 259:5287-5294, 1984.
Weiner et al., "A point mutation in the neu oncogene mimics ligand induction of receptor aggregation," Nature 339:230234, 1989.
Wada et al, "Intermolecular Association of the p185.sup.neu Protein and EGF Receptor Modulates ECF Receptor Function," Cell 61:1339-1347, 1990.
Di Fiore et al., "Overexpression of the Human EGF Receptor Confers on EGF-Dependent Transformed Phenotype to NIH 3T3 Cells," Cell 51;1063-1070, 1987.
Kokai et al., "Phosphorylation Process Induced by Epidermal Growth Factor Alters the Oncogenic and Cellular Neu NGL Gene Products," Biological Abstracts BA86:91443, 1988.
Stern et al., "EGF-Stimulated Tyrosine Phosphorylation of P185N-E-U A Potential Model for Receptor Interactions," Biological Abstracts BA87:44442, 1988.
Yarden et al., "Epidermal Growth Factor Induces Rapid, Reversible Aggregation of the Purified Epidermal Growth Factor Receptor," Biochem. 26:1443-1451, 1987.
Kokai et al., "Synergistic Interaction of p185c-neu and the EGT Receptor Leads to Transformation of Rodent Fibroblasts," Cell 58:287-292, 1989.
Bishayee et al, "Ligand-induced Dimerization of the Platelet-derived Growth Factor Receptor," J. of Biol. Chem. 264:11699-11705, 1989.
Drebin et al., "Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene," Nature 312:545-548, 1984.
Yarden et al, "Growth Factor Receptor Tyrosine Kinases," Ann. Rev. Biochem. 57:443-78, 1988.
Maguire et al., "Distribution of neu (c-erbB-2) Protein in Human Skin," Investigative Dermatology 92:786-790, 1989.
Cohen et al., "Expression pattern of the neu (NGL) gene-encoded growth factor receptor protein (p185.sup.neu) in normal and transformed epithelial tissues of the digestive tract," Oncogene 4:81-88, 1989.
Kokai et al., "Stage- and tissue-specific expression of the neu oncogene in rat development," Proc. Natl. Acad. Sci. USA 84:8498-8501, 1987.
Greene et al., "Receptor Systems in Tissues of the Nervous System," Immunological Reviews No. 100. Dec. 1987.
Davis James G.
Dobashi Kunio
Greene Mark I.
Hamuro Junji
Scheiner Toni R.
Trustees of the University of Pennsylvania
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