Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-12-22
2002-07-23
Huff, Sheela (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S004000, C435S007100, C435S007210, C435S007230, C435S029000, C435S030000, C436S063000, C436S064000
Reexamination Certificate
active
06423494
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to chemotherapy and drug resistance.
Cancer chemotherapy commonly involves the administration of one or more cytotoxic or cytostatic drugs to a patient. The goal of chemotherapy is to eradicate a substantially clonal population (tumor) of transformed cells from the body of the individual, or to suppress or to attenuate growth of the tumor. Tumors may occur in solid or liquid form, the latter comprising a cell suspension in blood or other body fluid. A secondary goal of chemotherapy is stabilization (clinical management) of the afflicted individual's health status. Although the tumor may initially respond to chemotherapy, in many instances the initial chemotherapeutic treatment regimen becomes less effective or ceases to impede tumor growth. The selection pressure induced by chemotherapy promotes the development of phenotypic changes that allow tumor cells to resist the cytotoxic effects of a chemotherapeutic drug.
SUMMARY OF THE INVENTION
The present invention concerns DR6, a gene which is expressed at a relatively high level in a number of drug resistant cancer cell lines. DR6 nucleic acids and polypeptides are useful in, for example, diagnostic methods related to identification of drug resistant cells (e.g., cancer cells). DR6 nucleic acids and polypeptides are also useful in screening methods directed to the identification of compounds that can modulated (increase or decrease) the drug resistance of a particular cell type or multiple cell types.
The DR6 1792 nucleotide cDNA described below (SEQ ID NO:1) has a 1263 open reading frame (nucleotides 96 to 1358 of SEQ ID NO:1; SEQ ID NO:3) which encodes a 421 amino acid protein (SEQ ID NO:2).
The invention features a nucleic acid molecule which is at least 45% (or 55%, 65%, 75%, 85%, 95%, or 98%) identical to the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, the nucleotide sequence of the cDNA insert of the plasmid deposited with ATCC as Accession Number (the “cDNA of ATCC PTA-1881”), or a complement thereof.
The invention features a nucleic acid molecule which includes a fragment of at least 15 (20, 25, 30, 150, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000, 1100, 1200 or 1266) nucleotides of the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, the nucleotide sequence of the cDNA ATCC PTA-1881, or a complement thereof.
The invention features a nucleic acid molecule which includes a nucleotide sequence encoding a protein having an amino acid sequence that is at least 80% (or 82%, 85%, 95%, or 98%) identical to the amino acid sequence of SEQ ID NO:2, or the amino acid sequence encoded by the cDNA of ATCC PTA-1881.
In an embodiment, a DR6 nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, or the nucleotide sequence of the cDNA of ATCC PTA-1881, or a complement thereof.
Also within the invention is a nucleic acid molecule which encodes a fragment of a polypeptide having the amino acid sequence of SEQ ID NO:2, the fragment including at least 15 (25, 30, 50, 100, 150, 200, 300, 400 or 421) contiguous amino acids of SEQ ID NO:2 or the polypeptide encoded by the cDNA of ATCC Accession Number PTA-1881.
The invention includes a nucleic acid molecule which encodes a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or the amino acid sequence encoded by the cDNA of ATCC Accession Number PTA-1881, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule comprising SEQ ID NO:1 or SEQ ID NO:3 under highly (or moderately) stringent conditions.
In general, an allelic variant of a gene will be readily identifiable as mapping to the same chromosomal location as the gene. For example, in Example 1, the chromosomal location of the human DR6 is shown to be chromosome 19, position 41-43 cM, near marker stSG4364. Thus, allelic variants of human DR6 will be readily identifiable as mapping to the human DR6 locus on chromosome 19 near genetic marker stSG4364.
Also within the invention is an isolated DR6 protein having an amino acid sequence that is at least about 80% (82%, 85%, 95%, or 98%) identical to the amino acid sequence of SEQ ID NO:2. The amino acid sequence of such DR6 proteins can include one or more (e.g., 2, 5, 10, 15, 30, 25, 30 or more) conservative amino acid substitutions. For example, 1%, 2%, 3%, 5%, 7%, 10%, or 15% of the amino acid residues can be replaced by conservative substitution.
Also within the invention is an isolated DR6 protein which is encoded by a nucleic acid molecule having a nucleotide sequence that is at least about 65%, preferably 75%, 85%, or 95% identical to SEQ ID NO:3 or the protein coding portion of the cDNA of ATCC PTA-1881.
Also within the invention is a polypeptide which is a naturally occurring allelic variant of a polypeptide that includes the amino acid sequence of SEQ ID NO:2 or an amino acid sequence encoded by the cDNA insert of the plasmid deposited with ATCC as Accession Number PTA-1881, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule comprising SEQ ID NO:1 or SEQ ID NO:3 under highly (or moderately) stringent conditions.
Another embodiment of the invention features DR6 nucleic acid molecules which specifically detect DR6 nucleic acid molecules. For example, in one embodiment, a DR6 nucleic acid molecule hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, or the cDNA of ATCC PTA-1881, or a complement thereof. In another embodiment, the nucleic acid molecule is at least 15 (20, 25, 30, 150, 100, 150, 200, 250 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000, 1100, 1200 or 1266) 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, the cDNA of ATCC PTA-1881, or a complement thereof. In yet another embodiment, the invention provides an isolated nucleic acid molecule which is antisense to the coding strand of a DR6 nucleic acid.
Another aspect of the invention provides a vector, e.g., a recombinant expression vector, comprising a DR6 nucleic acid molecule of the invention. In another embodiment the invention provides a host cell containing such a vector or an isolated DR6 nucleic acid molecule. The invention also provides a method for producing DR6 protein by culturing, in a suitable medium, a host cell of the invention containing an isolated nucleic acid molecule or recombinant expression vector such that a DR6 protein is produced.
Another aspect of this invention features isolated or recombinant DR6 proteins and polypeptides. Preferred DR6 proteins and polypeptides possess at least one biological activity possessed by naturally occurring human DR6 protein, e.g., (1) the ability to form protein:protein interactions with membrane proteins; (2) the ability to form protein-protein interactions with a clatherin; (3) the ability to bind a DR6 ligand; (4) and the ability to increase drug resistance.
The DR6 proteins of the present invention, or biologically active portions thereof, can be operatively linked to a non-DR6 polypeptide (e.g., heterologous amino acid sequences) to form a DR6 fusion protein. The invention further features antibodies that specifically bind DR6 proteins, such as monoclonal or polyclonal antibodies. In addition, DR6 proteins or biologically active portions thereof can be incorporated into pharmaceutical compositions, which optionally include pharmaceutically acceptable carriers.
In another aspect, the present invention provides a method for detecting the presence of DR6 activity or expression in a biological sample by contacting the biological sample with an agent capable of detecting an indicator of DR6 activity such that the presence of DR6 activity is detected in the biological sample. For example, the invention includes a method for detecting the presence of a DR6 polypeptide in a sample. This method features the steps of contacting
Jin Shengfang
Shyjan Andrew W.
Van Huffel Christophe
Fish & Richardson P. C.
Harris Alana M.
Huff Sheela
Millennium Pharmaceuticals Inc.
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