Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1997-12-16
2001-08-28
Ulm, John (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S069100, C435S252300, C435S320100, C530S350000, C536S023500
Reexamination Certificate
active
06280955
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of this invention is proteins involved in IL-1-mediated cell signal transduction.
2. Background
Interleukin-1 (IL-1) plays a central role in the generation of inflammatory responses (1). After binding to the cell surface receptor IL-1RI, IL-1 activates intracellular signaling cascades leading to the activation of the transcription factor NF-&kgr;B, which in turn upregulates the expression of many proinflammatory genes in the nucleus (1, 2). Although considerable progress has been made recently in delineating IL-1 signaling mechanism, our understanding of the process(es) remains incomplete. Within seconds after cells are exposed to IL-1, IL-1 receptor associated kinase (IRAK) is recruited in the IL-1 receptor complex where it becomes highly phosphorylated (3). Subsequently, IRAK interacts with TRAF6, a TRAF family member required for IL-1 mediated NF-&kgr;B activation (4). IRAK and IL-IRI do not interact directly with one another in mammalian cells when the two proteins are coexpressed, nor do they interact in the yeast two hybrid system (8).
We have found a protein, IL-1R accessory protein, IL-1RAcP, that is necessary for the recruitment of IRAK to the receptor complex. IL-1RAcP is a transmembrane protein that shares 25% sequence identity with IL-1RI and is required for IL-1 signal transduction (10). IL-1RAcP does not bind directly to IL-1, but it can be cross-linked to radiolabeled ligands in the presence of IL-1RI (9). To address the role of IL-1RAcP, we isolated a human IL-1RAcP cDNA from a placenta cDNA library and used this protein to identify polypeptides having human-specific IL-1RAcP structure and function.
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SUMMARY OF THE INVENTION
The invention provides methods and compositions relating to isolated IL-1RAcP polypeptides, related nucleic acids, polypeptide domains thereof having IL-1RAcP-specific structure and activity and modulators of IL-1RAcP function, particularly MYD88 binding activity and phosphorylation of IL-1RAcP. IL-1RAcP polypeptides can regulate NF&kgr;B activation and thus are important regulators of cell function. The polypeptides may be produced recombinantly from transformed host cells from the subject IL-1RAcP polypeptide encoding nucleic acids or purified from mammalian cells. The invention provides isolated IL-1RAcP hybridization probes and primers capable of specifically hybridizing with the disclosed IL-1RAcP gene, IL-1RAcP -specific binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis (e.g. genetic hybridization screens for IL-1RAcP transcripts), therapy (e.g. IL-1RAcP inhibitors to inhibit IL-1 signal transduction) and in the biopharmaceutical industry (e.g. as immunogens, reagents for isolating other transcriptional regulators, reagents for screening chemical libraries for lead pharmacological agents, etc.).
REFERENCES:
patent: WO 96/23067 (1996-01-01), None
Osman Richard Aron
Tularik Inc.
Ulm John
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