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Regulators of type-1 tumor necrosis factor receptor and other cytokine receptor shedding

a type-1 tumor necrosis factor and cytokine receptor technology, applied in the direction of immunoglobulins against animals/humans, peptides, enzymology, etc., can solve the problems of rheumatoid arthritis, tissue injury and chronic inflammatory diseases,

Inactive Publication Date: 2007-03-15
THE GOVERNMENT OF THE USA OF AMERICA REP BY THE SEC DEPT OF HEALTH & HUMAN SERVICES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides compositions and methods related to regulating the shedding of cytokine receptors through the TNF pathway, as well as other signaling pathways controlled by other cytokines. This approach can be used for the treatment of diseases and disorders of the immune system. The invention includes isolated nucleic acids and polypeptides that promote the shedding of the extracellular domain of TNF receptor 1 (TNFR1), as well as recombinant vectors and antibodies that target this pathway. The invention also provides methods for regulating the shedding of other cytokine receptors, such as type-1 tumor necrosis factor receptor, type I interleukin-1 cytokine receptor, typeII interleukin-1 cytokine receptor, and interleukin-6 cytokine receptor alpha-chain gp80. Overall, the invention provides tools for controlling the shedding of cytokine receptors and offers potential for therapeutic applications in the treatment of immune system diseases and disorders.

Problems solved by technology

It is theorized that these pathologies result from the aberrant regulation of TNF activity, in which the pathologies manifest as a result of excessive or insufficient TNF activity.
Among the activities for which TNF is most noted are its pro-inflammatory actions, sometimes termed the “acute phase immune response.” Unfortunately, if not properly regulated, these proinflammatory responses can result in tissue injury and chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, septic shock, cachexia, autoimmune disorders, graft-versus-host disease and insulin resistance (Piguet et al, J. Exp. Med., 166:1280 ; Pujol-Borrell et al, Nature 326:304-306 ; Tracey et al, Nature 330:662-664 ; Oliff, Cell 54:141-142 ; Vilcek et al, J.

Method used

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  • Regulators of type-1 tumor necrosis factor receptor and other cytokine receptor shedding
  • Regulators of type-1 tumor necrosis factor receptor and other cytokine receptor shedding
  • Regulators of type-1 tumor necrosis factor receptor and other cytokine receptor shedding

Examples

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example 1

Identification of ARTS-1, a Novel Human Aminopeptidase Regulator of Type-1 Tumor Necrosis Factor Receptor (TNFR1) Shedding

A) Yeast Two-Hybrid Library Screening

[0319] A yeast two-hybrid library screening was conducted to identify proteins that interact with or are capable of interacting with the extracellular domain of the type I, 55 kDa TNF receptor (TNFR1). A human lung cDNA library (Clontech), cloned into pGADIO (GAL4 DNA-activation domain vector), was screened to detect interactions with a GAL4BD-TNFR1 fusion protein using a Matchmaker System 2 (Clontech) using methods known in the art as well as the manufacturer's recommended protocols. Amino acids 26 to 216 of TNFR1, corresponding to the extracellular domain (i.e., the ectodomain) located between the putative leader domain and the transmembrane domain (Nophar et al, EMBO J., 10:3269-3278 [1990]) were cloned into pAS2-1 (GAL4 DNA-binding domain vector) to generate the bait GAL4 DNA-binding domain fusion protein, GAL4BD-TNFR1....

example 2

Molecular Analysis of the ARTS-1 cDNA and Predicted Polypeptide

[0323] The complete cDNA corresponding to the human ARTS-1 transcription unit contains 4845 nucleotides and encodes an open reading frame of 2823 bp, as shown in FIG. 1 and set forth in SEQ ID NO:1. The first in-frame ATG codon, located at nucleotide 88, follows an in-frame stop codon, located at nucleotide 76, and matches the −3 and +4 nucleotides of the consensus Kozak sequence consistent with a strong initiator codon (aagatgg) (Kozak, J. Cell Biol, 108:229-241 [1989]). Sequence analysis revealed five potential N-glycosylation sites and a TAA stop codon, located at nucleotide 2911. The putative 3′ untranslated region contained a consensus polyadenylation site (AATAAA), located at nucleotides 4876 to 4800, which is 18 nucleotides upstream of a 27 nucleotide poly(A) tail. The 3′ untranslated region also included two ATTTA sites, located at nucleotides 3929 and 4457; this sites have been identified as an mRNA destabiliza...

example 3

ARTS-1 mRNA Expression Analysis

[0327] Following analysis of the ARTS-1 cDNA, the expression pattern of endogenous of ARTS-1 mRNA was investigated using a Northern immunoblotting protocol. RT-PCR was performed on human lung poly(A+) mRNA (Clontech) to generate the human ARTS-1 cDNA coding sequence utilizing the following primers:

(SEQ ID NO:5)5′-GCAAGAAGATGGTGTTTCTGCCCCTC-3′ (80-105)and(SEQ ID NO:6)5′-TTACATACGTTCAAGCTTTTCACT-3′ (2890-2913).

The full length ARTS-1 coding sequence amplified by these primers was cloned into the pTarget mammalian expression vector (Promega). The DNA sequence of this cloned open reading frame was obtained from both strands by automated fluorescent sequencing, as known in the art. There were no discrepancies between the sequence obtained from these two strands, nor from the sequence obtained from the PMA-stimulated NCI-H292 cell line cDNA library. A 32P-labelled cDNA probe, corresponding to the full length ARTS-1 coding sequence, was utilized as a probe...

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Abstract

The present invention provides compositions and methods for the regulation of cytokine signaling through the Tumor Necrosis Factor (TNF) pathway. Specifically, the invention provides a novel gene, polypeptide and related compositions and methods for the regulation of ectodomain shedding. In preferred embodiments, methods and compositions for the regulation of TNF Type-1 Receptor ectodomain shedding are provided. The present invention finds use in therapeutics, diagnostics, and drug screening applications.

Description

[0001] This application is a divisional of copending U.S. patent application Ser. No. 10 / 220,443, filed Dec. 19, 2002; which is a national stage application of PCT / US01 / 06464, filed Feb. 28, 2001; which is an application claiming the benefit under 35 USC 119(e) of U.S. Provisional Patent Application No. 60 / 185,586, filed Feb. 28, 2000. [0002] This invention was made during the course of work supported by the United States Government under the National Institutes of Health. As such, the United States Government may have certain rights to this invention.FIELD OF THE INVENTION [0003] The present invention provides compositions and methods related to regulation of cytokine signaling through the Tumor Necrosis Factor (TNF) pathway. Specifically, the invention provides novel genes, polypeptides and related compositions and methods for the regulation of TNF Type-1 Receptor ectodomain shedding. It is contemplated that the compositions and methods of the present invention will also find use ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68C07H21/04C12P21/06C07K14/715C07K16/28A61K38/00A61K39/00A61K48/00C07K16/40C12N9/64C12N15/113C12N15/57C12Q1/6883
CPCA61K38/00A61K39/00A61K48/00C07H21/04C07K14/7151C12Q2600/158C12N9/6421C12N15/1133C12Q1/6883C12Q2600/136C07K16/40
Inventor LEVINE, STEWART
Owner THE GOVERNMENT OF THE USA OF AMERICA REP BY THE SEC DEPT OF HEALTH & HUMAN SERVICES
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