Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
2001-03-16
2004-11-02
McGarry, Sean (Department: 1635)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C435S325000, C435S366000, C435S091500, C435S023000, C435S024000, C435S024000
Reexamination Certificate
active
06812326
ABSTRACT:
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims.
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins contribute to signal transduction induced by TNF receptor family signaling. TRAF3 cloned as binding protein to the cytoplastic domain of CD40, a member of TNF receptor superfamily, is believed to be involved in signaling pathway induced by CD40, Lymphotoxin (LT) &bgr; receptor, CD30 ligation (1-7). Here we report molecular cloning of a novel TRAF-interacting protein named as TREX because of TRAF-interacting EXT (hereditary multiple exostoses) gene family protein. TREX has highly homologous sequence to the EXT gene family, a candidate of tumor suppressor gene. TREX strongly interacts with TRAF2 and TRAF3, and TREX and TRAF protein colocalize in mammalian cells. Moreover, overexpression of TREX modulates NF-kB activity induced by TRAF-mediated signaling. These findings indicate that TREX and the other EXT gene family proteins can function as a mediator in receptor signaling and could be involved in tumorigenesis.
SUMMARY OF THE INVENTION
This invention provides an isolated nucleic acid molecule encoding a Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein.
This invention provides an isolated nucleic acid molecule encoding a mutant homolog of the mammalian Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein whose mutant sequences (genetic alterations) are shown in Table 3 infra.
This invention provides a vector comprising the isolated nucleic acid molecule encoding a Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein.
This invention provides a purified mammalian Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein.
This invention provides a protein comprising substantially the amino acid sequence set forth in
FIG. 1A
(SEQ ID NOS: 2 and 4).
This invention provides an oligonucleotide comprising a nucleic acid molecule of at least 15 nucleotides capable of specifically hybridizing with a unique sequence included within the sequence of an isolated nucleic acid molecule encoding a Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein.
This invention provides an antisense oligonucleotide comprising a sequence capable of specifically hybridizing with a unique sequence included within an mRNA molecule encoding a Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein.
This invention provides an antisense oligonucleotide comprising a sequence capable of specifically hybridizing with a unique sequence included within a genomic DNA molecule encoding a Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein.
This invention provides a monoclonal antibody directed to an epitope of a Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein.
This invention provides a method of inhibiting TREX protein interaction with a TRAF protein comprising administering a ligand comprising an amino acid domain which binds to a EXT C domain of the TREX protein so as to inhibit binding of the TREX protein to the TRAF protein.
This invention provides a method of inhibiting overexpression of TREX protein comprising administering any of the above-described antisense oligonucleotides which bind to an mRNA molecule encoding a human Tumor necrosis factor
Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein so as to inhibit overexpression of the human TREX protein.
This invention provides a method of inhibiting growth of a tumor cell comprising blocking a TRAF interacting site of a TREX protein by administering a ligand capable of binding to the TRAF interacting site of a TREX protein.
This invention provides a pharmaceutical composition comprising an amount of any of the above-described oligonucleotides effective to prevent overexpression of a TREX protein and a pharmaceutically acceptable carrier capable of passing through a cell membrane.
This invention provides a pharmaceutical composition comprising an amount of any of the above-described antibodies effective to block binding of a TREX protein to a TRAF protein and a pharmaceutically acceptable carrier capable of passing through a cell membrane.
This invention provides a method of treating an abnormality in a subject, wherein the abnormality is alleviated by the inhibition of binding of a TREX protein and a TRAF protein which comprises administering to the subject an effective amount of the above described pharmaceutical composition effective to block binding of the TREX protein and the TRAF protein in the subject, thereby treating the abnormality in the subject.
This invention provides a method of treating an abnormality in a subject, wherein the abnormality is alleviated by the inhibition of overexpression of a TREX protein which comprises administering to the subject an effective amount of the above-described pharmaceutical composition effective to inhibit overexpression of the TREX protein, thereby treating the abnormality in the subject. In a preferred embodiment the abnormality is cancer, a hereditary multiple extosis or an autoimmune disease.
This invention provides a method of screening for a chemical compound which inhibits TREX protein and TRAF protein binding comprising: (a) incubating the chemical compound with a TREX protein and a TRAF protein; (b) contacting the incubate of step (a) with an affinity medium under conditions so as to bind a TREX protein-TRAF protein complex, if such a complex forms; and (c) measuring the amount of the TREX protein-TRAF protein complex formed in step (b) so as to determine whether the compound is capable of interfering with the formation of the complex between the TREX protein-TRAF protein.
This invention provides a method of preventing inhibition of a CD40 signal-dependent NF-kB activation comprising administering any of the above-described antisense oligonucleotides which bind to an mRNA molecule encoding a human Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein so as to prevent inhibition of CD40 signal-dependent NF-kB activation.
This invention provides a method of preventing inhibition of activation of a CD40 signal-dependent NF-kB comprising administering a ligand comprising an amino acid domain which binds to a EXT C domain of the TREX protein so as to inhibit binding of the TREX protein to the TRAF protein, thereby preventing inhibition of activation of a CD40 signal-dependent NF-kB.
This invention provides a method of preventing upregulation of a TNF receptor typeII signal-dependent NF-kB activation comprising administering any of the above-described antisense oligonucleotides which bind to an mRNA molecule encoding a human Tumor necrosis factor Receptor-Associated Factor (TRAF) protein-interacting hereditary multiple extoses (TREX) protein so as to prevent upregulation of a TNF receptor typeII (TNFRII) signal-dependent NF-kB activation.
This invention provides a method of preventing upregulation of activation of a TNF receptor typeII (TNFRII)-signal-dependent NF-kB comprising administering a ligand comprising an amino acid domain which binds to a EXT C domain of the TREX protein so as to inhibit binding of the TREX protein to the TRAF protein, thereby preventing upregulation of activation of a TNF recep
Cooper & Dunham LLP
McGarry Sean
Schultz James D.
The Trustees of Columbia University in the City of New York
White John P.
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