Calcium-binding protein

Details Calcium-binding protein Calcium-binding protein

1998-12-07

2001-02-27

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S350000, C435S070210, C435S326000

Reexamination Certificate

active

06194385

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of a novel calcium-binding protein and to the use of these sequences in the diagnosis, prevention, and treatment of disorders associated with cell proliferation.
BACKGROUND OF THE INVENTION
Calcium plays essential roles in various cell processes including cell metabolism, muscle contraction, molecular secretion and mitogenesis. Calcium is mostly stored in endoplasmic reticulum (ER) in non-muscle cells, and in the sarcoplasmic reticulum (SR) in muscle cells. The regulation of calcium involves a family of homologous, calcium-binding proteins such as calbindins, troponin C, calmodulin, and S-100 proteins. These proteins contain a common structural motif, the EF-hand motif, which consists of two &agr;-helices separated by a loop of 12 to 13 amino acid residues.
Some proteins identified in the lumen of ER, such as BiP, protein disulfide isomerase, calreticulin, and endoplasmin, are also involved in the regulation of calcium. These proteins do not have the EF-hand motif; they are retained in the lumen by a membrane-bound receptor. The receptor retrieves the luminal ER proteins from Golgi apparatus to the ER lumen by recognizing their carboxy-terminal tetrapeptide, Lys-Asp-Glu-Leu (KDEL) or His-Asp-Glu-Leu (HDEL). An exception to these ER proteins is reticulocalbin, a lumenal protein of the ER which possesses both the EF-hand motif and the ER-retention signal, HDEL (Ozawa, M. and Muramatsu, T. (1993) J. Biol. Chem. 268:699-705; Ozawa, M. (1995) J. Biochem. 117: 1113-1119). In fact, the mouse reticulocalbin, a 44 kDa protein, has six repeats of the EF-hand motif. The human reticulocalbin, which shares 95% identity with its mouse homolog, was cloned using the mouse gene (Ozawa, supra).
The discovery of a novel calcium-binding protein similar to reticulocalbin and the polynucleotide which encodes it satisfies a need in the art by providing new compositions which are useful in diagnosing, preventing, and treating disorders associated with cell proliferation.
SUMMARY OF THE INVENTION
The present invention features a novel calcium-bind protein hereinafter designated HCBP and characterized as having similarity to a calcium-binding protein, reticulocalbin.
Accordingly, the invention features a substantially purified HCBP having the amino acid sequence shown in SEQ ID NO:1.
One aspect of the invention features isolated and substantially purified polynucleotides that encode HCBP. In a particular aspect, the polynucleotide is the nucleotide sequence of SEQ ID NO:2.
The invention also relates to a polynucleotide sequence comprising the complement of SEQ ID NO:2 or variants thereof. In addition, the invention features polynucleotide sequences which hybridize under stringent conditions to SEQ ID NO:2.
The invention additionally features nucleic acid sequences encoding polypeptides, oligonucleotides, peptide nucleic acids (PNA), fragments, portions or antisense molecules thereof, and expression vectors and host cells comprising polynucleotides that encode HCBP. The present invention also features antibodies which bind specifically to HCBP, and pharmaceutical compositions comprising substantially purified HCBP. In addition, the invention features methods for stimulating cell proliferation using HCBP and for treating or preventing a disorder associated with cell proliferation using an antagonist of HCBP.


REFERENCES:
Ozawa. Accession No. JC4173 from PIR-58 protein database, Aug. 1995.
Ozawa, M. et al., “Reticulocalbin, a Novel Endoplasmic Reticulum Resident Ca2+-binding Protein with Multiple EF-hand Motifs and a Carboxyl-terminal HDEL Sequence.”J.Biol.Chem.(1993) 268(1):699-705. (GI 220581 and GI 220582).
Ozawa, M. “Cloning of a Human Homologue of Mouse Reticulocalbin Reveals Conservation of Structural Domains in the Novel Endoplasmic Reticulum Resident Ca2+-Binding Protein with Multiple EF-Hand Motifs.”J.Biochem.(1995) 117:1113-1119. (GI 1262328 and GI 1262329).
Asakura, K., et al., “Clone Rem1, ORF, fragment,” TRROD EMBL Database Entry Q63399, Accession No. Q63399, XP002070130, Nov. 1, 1996.
Hillier, L., et al., “Homo sapienscDNA clone 376349 5′ similar to PIR:JC4173 reticulocalbin homolog-human,” EMEST EMBL Database Entry HSA41328, Accession No. AA041328, XP002070131, Sep. 1, 1996.
Hillier, L., et al., “Homo sapienscDNA clone 664259 5′ similar to TR:G780361,” EMEST EMBL Database entry HS1150166, Accession No. AA232452, XP002070132, Mar. 6, 1997.
Hillier, L., et al., “Homo sapienscDNA clone 811903 5′ similar to SW:RCA1 mouse Q05186 reticulocalbin precursor,” EMEST EMBL Database entry HS1246269, Accession No. AA456267, XP002070133, Jun. 7, 1997.
Hillier, L., et al., “Mus musculuscDNA clone 420903 5′ similar to PIR:JC4173 reticulocalbin homolog-human,” EMEST EMBL Database entry MMW02, Accession No. W91002, XP002070134, Jul. 9, 1996.
Marra, M., et al., “Mus musculuscDNA clone 386402 5′ similar to GB:D13003Mus musculusreticulocalbin mRNA, complete CDs,” EMEST EMBL Database entry MM38328, Accession No. W64383, XP002070135, Jun. 11, 1996.
Marra, M., et al., “Mus musculuscDNA clone 463711 5′ similar to PIR:JC4173 reticulocalbin homolog-human,” EMEST EMBL Database entry MMA28649, Accession No. AA028649, XP002070136, Aug. 17, 1996.

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