Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-03-17
2001-02-27
Martinell, James (Department: 1632)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S069100, C435S325000, C435S252300, C435S320100, C536S023100, C536S023500
Reexamination Certificate
active
06194151
ABSTRACT:
BACKGROUND OF THE INVENTION
The tumor necrosis factor receptor (TNFR) superfamily of proteins encompasses over a dozen members, most of which are type I transmembrane proteins, related by the presence of conserved cysteine-rich repeats (CRRs) in their N-terminal cysteine-rich domains (CRDs). Members of the TNFR superfamily include TNFRI (p55), TNFR2 (p75), TNFR3 (TNF-RP), Fas (also known as CD95 and Apol ), OX-40, 41 -BB, CD40, CD30, CD27, OPG, and p75 NGFR. (Smith et al. (1993)
Cell
76:959-962; Armitage, R. J. (1994)
Curr. Opin. Immunol.
6:407-413; Gruss et al. (1995)
Blood
85, 3378-3404; Baker et al. (1996)
Oncogene
12:1-9; and Simonet et al. (1997)
Cell
89:309-319.) A TNFR superfamily member is typically a membrane-bound, trimeric or multimeric complex which is stabilized via intracysteine disulfide bonds that are formed between the cysteine-rich domains of individual subunit members (Banner et al. (1993)
Cell
73:431-445). The proteins themselves do not have intrinsic catalytic activity, rather they function via association with other proteins to transduce cellular signals.
Most members of the TNFR superfamily recognize ligands that play critical roles as costimulators in immune responses. However, a subset of TNFR superfamily members have been determined to play a key role in the extracellular regulation of cell death. Induction of cell death requires a unique cytoplasmic motif which was originally identified in TNFRI and Fas and termed the “death domain” (Tartaglia et al. (1993)
Cell
74:845-853 and Itoh and Nagata (1993)
J. Biol. Chem.
268:10932-10937). Using the yeast two-hybrid method to clone genes encoding proteins that associate with the cytoplasmic domains of TNFRL or Fas, three dramatically different genes were identified (TRADD in Hsu et al (1995) Cell 81:495-504; FADD in Chinnaiyan et al. (1995)
Cell
81:501-512; and RIP in Stanger et al. (1995)
Cell
81:512-523). FADD was independently cloned with the same strategy, and termed MORT
1
(Boldin et al. (1995)
J. Biol. Chem.
270:7795-7798.) In fact, the only structural similarity between these proteins was the shared motif that has homology with the death domains of the TNFRI and Fas receptors. Death domains have recently been identified in a variety of proteins including, for example, the ankyrins, the
Drosophila
proteins PELLE and TUBE, DAP kinase, mouse myD88. (For review see Feinstein and Kimchi (1995)
Trends. Biochem. Sci.
20:342-344; Golstein et al. (1995)
Cell
81:185-186; Cleveland and Ihle (1995)
Cell
81:479-482; and Hofinan and Tschopp (1995)
FEBS Lett.
371:321-323). Moreover, the death domain has been implicated in protein:protein interactions between two proteins each containing such a domain. Such a death domain:death domain interaction is believed to be a crucial component of the cellular signal transduction pathways that lead to cell death, thus, implicating members of the TNFR superfamily in a wide range of signal transduction with appreciably diverse outcomes.
Aside from the membrane-bound forms of TNFR superfamily proteins that function as cellular signal transducers, a functional TNFR superfamily protein can also exist in a soluble form. Soluble versions of the superfamily bind cognate ligands and influence bioavailability. For instance, the osteoprotegerin protein family exists as a soluble protein (Simonet et al. (1997)
Cell
89:309-319). Many soluble forms of the TNFR have been identified. Certain soluble TNFRs are elevated in disease states such as lupus and rheumatoid arthritis (Gabay et al. (1997)
J. Rheumatol.
24(2):303-308). The soluble superfamily members lack the transmembrane domain characteristic of the majority of superfamily members due to either proteolytic cleavage or, at least in one instance, to alternative splicing (Gruss et al. (1995)
Blood
85, 3378-3404).
Given the important role of proteins of the TNFR superfamily, including both soluble as well as membrane-bound family members, in a wide range of cellular signal transduction pathways, there exists a need for identifying novel members of the TNFR superfamily as well as for modulators of such molecules for use in regulating a variety of cellular responses.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of novel molecules of the TNF receptor superfamily, referred to herein as TNF receptor-like “TRL” nucleic acid and protein molecules. The TRL molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding TRL proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of TRL-encoding nucleic acids. In one embodiment, an isolated nucleic acid molecule of the present invention preferably encodes a TRL protein which includes a cysteine-rich domain, a C-terminal unique domain and is membrane bound or secreted. In another embodiment, the nucleic acid molecule is a naturally occurring nucleotide sequence.
In another embodiment, a nucleic acid molecule of the invention is 60% homologous to the nucleotide sequence shown in SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:22, the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98649, or a complement thereof and, preferably, encodes a TRL protein. In yet another embodiement, the isolated nucleic acid molecule is 60% homologous to the nucleotide sequence shown in SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:24, or a complement thereof and, preferably, encodes a TRL protein. In a preferred embodiment, the isolated nucleic acid molecule encodes the amino acid sequence of human or mouse TRL protein.
In another embodiment, the isolated nucleic acid includes a nucleotide sequence encoding a protein having an amino acid sequence sufficiently homologous to a cysteine-rich domain amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or SEQ ID NO:23 and, preferably, encodes a TRL protein. In a preferred embodiment, the nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:24. In another preferred embodiment, the nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:22, or the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98649.
Another embodiment of the invention features isolated nucleic acid molecules which specifically detect TRL nucleic acid molecules relative to nucleic acid molecules encoding other TNFR superfamily molecules. For example, in one embodiment, the nucleic acid molecule hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in nucleotides 480 to 1165 of SEQ ID NO: I or nucleotides 455 to 2155 of SEQ ID NO:3. In another embodiment, the nucleic acid molecule is at least 500 nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:22, the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98649, or a complement thereof
In a preferred embodiment, an isolated nucleic acid molecule comprises nucleotides 344-2062 of SEQ ID NO: 1 or a complement thereof. In another embodiment, the nucleic acid molecule firther comprises nucleotides 1-343 of SEQ ID NO: 1. In yet another preferred embodiment, the nucleic acid molecule further comprises nucleotides 2063-3331 of SEQ ID NO:1.
In another preferred embodiment of the invention, an isolated nucleic acid molecule comprises nucleotides 190-948 of SEQ ID NO:3 or a complement thereof. In another embodiment, the nucleic acid molecule further comprises nucleotides 1-189 of SEQ ID NO:3. In yet another preferred embodiment, the nucleic acid molecule further comprises nucleotides 949-2612 of SEQ ID NO:3.
In another preferred embodiment of the invention, an isolated nucleic acid molecule comprises nu
Lahive & Cockfield LLP
Martinell James
Milasincic Debra J.
Millenium Pharmaceuticals, Inc.
Smith DeAnn F.
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