Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-03-26
2001-06-12
Huff, Sheela (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S004000, C435S007100, C435S007900
Reexamination Certificate
active
06245522
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to cellular regulation, and more particularly to cell signaling in cell proliferative disorders.
BACKGROUND OF THE INVENTION
PINCH (Particularly Interesting New Cys-His protein) is a LIM-only protein consisting primarily of five LIM domains. The LIM motif, recognized in 1990 in the lin-11, isl-1 and mec 3 proteins, specifies a double zinc finger domain which has been shown to participate in protein-protein interactions. Within the LIM family PINCH has the largest number of LIM domains (five), giving rise to ten zinc fingers.
The function of LIM domain proteins as adapters and modifiers in protein interactions has been reviewed recently. PINCH likely functions as an adapter protein for signal transduction. Adapter molecules such as PINCH can control the location, assembly and function of signaling networks, and may be constitutively-anchored to a particular subcellular localization or may be recruited to a signaling site. Because PINCH is associated with &bgr;1 integrin, a protein localized to the plasma membrane, it is reasonable to assume that PINCH functions as an anchoring adapter protein, targeting signaling components to sites of signal transduction at the cell membrane.
The PINCH signaling complex also contains the integrin-linked kinase (ILK), a serine-threonine kinase that associates with the cytoplasmic tails of integrins &bgr;1 and &bgr;3. ILK is involved in integrin-mediated signaling as well as in the &bgr;-catenin/LEF-1 signaling pathway, participating in the complex signaling interactions that occur at cell-matrix and cell-cell junctions. ILK may function in crosstalk between cell-matrix and cell-cell junctions and also with components of the Wnt signaling pathway.
ILK has been shown to have oncogenic properties. ILK-over expressing cells are tumorigenic in nude mice. The mechanisms by which ILK up regulation leads to a transformed phenotype are as yet poorly understood, but the available information points to effects on the nucleus. ILK over expression leads to up regulation of specific cell-cycle associated proteins and to the translocation of &bgr;-catenin from the cell membrane to the nucleus where it forms a complex with the transcription factor LEF-1. Because ILK over expression in cultured epithelial cells leads to enhanced fibronectin matrix assembly (a feature of mesenchymal cells), it is possible that ILK over expression in epithelial cells is associated with activation of mesenchymal gene expression.
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting a cell signaling disorder comprising administering to a subject a composition containing an agent which regulates a PINCH polypeptide or PINCH expression. The method is useful in inhibiting a cell proliferative disorder.
In one embodiment the invention provides a method of diagnosing a cell proliferative disorder in a subject associated with PINCH by determining the level of PINCH in the sample and comparing the level of PINCH in the sample to the level of PINCH in a standard sample, wherein an elevated level of PINCH is indicative of a cell proliferative disorder.
In another embodiment, the invention provides a method of ameliorating a cell proliferative disorder associated with PINCH, comprising treating a subject having the disorder with an agent that regulates PINCH activity or expression. The agent can be an antibody, polypeptide, antisense molecule or chemical.
In a further embodiment, the invention provides a method for identifying a compound which modulates cell proliferation, by contacting a sample containing PINCH polypeptide with a compound suspected of having PINCH modulating activity and detecting an effect on cell proliferation.
The invention also provides a method for identifying a cell proliferative disorder in a subject comprising, quantifying the expression of PINCH, ILK, or a combination thereof and correlating the level of expression with the presence of a cell proliferative disorder, wherein an elevated level of PINCH is indicative of a cell proliferative disorder and wherein an elevated level of ILK is indicative of a metastatic cell proliferative disorder.
In another embodiment, the invention provides a method for detecting a cell proliferative disorder in a subject, comprising, quantifying expression of polynucleotides encoding PINCH, ILK or a combination thereof wherein the polynucleotide level determines the presence of the cell proliferative disorder.
In yet another embodiment, the invention provides a method for detecting a cell proliferative disorder in a subject comprising quantifying PINCH polypeptide, ILK polypeptide or a combination thereof, wherein the levels of PINCH and ILK when compared to a standard sample are indicative of the presence of a cell proliferative disorder.
In yet another embodiment the invention provides a method of diagnosing breast cancer in a subject comprising detecting PINCH in cells isolated from the subject, wherein an elevated amount of PINCH when compared to a standard sample is indicative of a breast caner.
Furthermore, the invention provides a method of diagnosing a metastatic breast cancer in a subject comprising detecting PINCH and ILK in cells isolated from the subject, wherein in an elevated amount of PINCH and ILK compared to a standard sample is indicative of a metastatic breast cancer.
The invention also provides a method of determining the prognosis of a patient having a cell proliferative disorder comprising determining the level of PINCH and ILK in cells of a patient and correlating the level with prognosis of the patient.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
REFERENCES:
patent: 5552529 (1996-09-01), Rearden
Gray Cary Ware & Freidenrich LLP
Haile Lisa A.
Huff Sheela
The Regents of the University of California
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