Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
1999-04-13
2004-10-05
Prouty, Rebecca E. (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C435S023000, C435S091500, C435S471000, C435S212000, C435S325000, C435S252300, C435S320100, C435S219000, C424S094650, C530S350000, C536S023200
Reexamination Certificate
active
06800473
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to novel identified polynucleotides (or nucleic acids) and polypeptides (or proteins) or salts thereof, as well as peptide fragments thereof; mutants and derivatives of said polynucleotides (or nucleic acids) or said polypeptides (or proteins); to methods for producing such polynucleotides (or nucleic acids) and polypeptides (or proteins) as well as such mutants and derivatives; to agonists and antagonists of said polypeptides (or proteins); to antibodies against said polypeptides (or proteins), especially monoclonal antibodies thereagainst; and to use of said polynucleotides (or nucleic acids), polypeptides (or proteins), mutants, derivatives, agonists and antagonists.
The present invention relates to novel proteins which belong to the papain family and are cysteine proteinase enzymes (the cysteine proteinase enzymes are expected to be involved in various normal cellular processes, including the turnover of intracellular proteins, prohormone activation, and bone remodeling and to play important roles in a variety of pathological conditions such as Alzheimer's disease, pulmonary emphysema, rheumatoid arthritis, muscular dystrophy, osteoporosis, neurodegenerative disease, and cancer invasion and metastasis), useful for such studies, particularly to novel human cathepsin proteins (or fragments thereof) or salts thereof and to genes encoding the proteins or fragments. More specifically, the present invention relates to novel human cysteine proteinase-type proteins having a papain-like structure at the active site, said cysteine proteinase protein being cloned from human brain cDNA libraries (the instant novel human cysteine proteinase protein is named “Cathepsin L2”); to DNA comprising a nucleotide sequence coding for said cysteine proteinase protein; to host cells transformed with said DNA; to processes for producing said human cysteine proteinase protein by said transformed cells and to applications of such proteins and nucleic acid fragments.
2. Description of the Related Art
The cysteine proteinases are a family of enzymes involved in many normal cellular processes, including the turnover of intracellular proteins, prohormone activation, and bone remodeling (Berti, P. J., et al., J. Mol. Biol., 246: 273 to 283, 1995). In addition, it has been suggested that these proteolytic enzymes play important roles in a number of pathological conditions such as Alzheimer's disease, pulmonary emphysema, rheumatoid arthritis, muscular dystrophy, osteoporosis, and cancer invasion and metastasis (Berti, P. J., et al., J. Mol. Biol., 246: 273 to 283, 1995; Berquin, I. M., et al., Perspect. Drug Discov. Des., 2: 371 to 388, 1994).
At present, eight human cysteine proteinases of the papain family have been isolated and characterized at the amino acid sequence level: cathepsin B (Chan, S. J., et al., Proc. Natl. Acad. Sci. U.S.A., 83: 7721-7725, 1986), cathepsin L (Gal, S., et al., Biochem. J., 253: 303-306, 1988), cathepsin H (Ritonja, A., et al., FEBS Lett., 228: 341-345, 1988), cathepsin S (Shi, G. P., et al., J. Biol. Chem., 267: 7258-7262, 1992), cathepsin C (Paris, A., et al., FEBS Lett., 369: 326-330, 1995), cathepsin O (Velasco, G., et al., J. Biol. Chem., 269: 27136-27142, 1994), cathepsin K (Inaoka, T., et al., Biochem. Biophys. Res. Commun., 206: 89-96, 1995) and cathepsin W (Linnevers, C., et al., FEBS Lett., 405: 253-259, 1997).
Furthermore, several groups have described the existence of additional cysteine proteinases including cathepsins S, M, N, P, and T, which were originally identified because of their degrading activity on specific substrates such as aldolase, collagen, proinsulin, or tyrosine aminotransferase, but whose characterization at the molecular level has not yet been reported (Pontremoli, S., et al., Arch. Biochem. Biophys., 214: 376-385, 1982; Maciewicz, R., et al., Biochem. J., 25: 433-440, 1988; Docherty, K., et al., Proc. Natl. Acad. Sci. U.S.A., 79: 4613-4617, 1982; Gohda, E., et al., J. Biol. Chem., 256: 2567-2572, 1981).
Structural comparisons between the different members of the cysteine proteinase family have shown that they are synthesized as preproenzymes, which are processed to the corresponding proenzymes and targeted to the lysosomes by the mannose 6-phosphate signal attached to them. However, in some cases, the precursors of these lysosomal enzymes escape from this processing pathway and continue along the secretory route, entering storage granules and finally being released into the extracellular space (Sloane, B. F., et al., Science, 212: 1151-1153, 1981). Amino acid sequence comparisons between all members of the family have revealed that they are not closely related; the percentage of identity between them is less than 50%. Nevertheless, in their amino acid sequences, all of them contain a series of amino acids that are absolutely conserved and essential for their catalytic activity (Berti, P. J., et al., J. Mol. Biol., 246: 273-283, 1995).
Because it seems clear that cysteine proteinases play essential roles in both normal and pathological conditions, including tumor processes, over the last few years, the possibility that additional, uncharacterized members of this family of proteolytic enzymes could be produced by human tumors has been examined. This search for new human cysteine proteinases led us to identify cathepsin O, which was originally cloned from a breast carcinoma but is widely distributed in human tissues (Velasco, G., et al., J. Biol. Chem., 269: 27136-27142, 1994). Furthermore, the cloning and characterization of human bleomycin hydrolase, a cytosolic cysteine proteinase that is distantly related to other members of the papain family and is involved in chemotherapy resistance, has recently been reported (Ferrando, A. A., et al., Cancer Res., 56: 1746-1750, 1996.).
SUMMARY OF THE INVENTION
It would be expected that the cysteine proteinases are not only involved in many normal cellular processes, including the turnover of intracellular proteins, prohormone activation, and bone remodeling but also play important roles in a number of diseases, disorders and pathological conditions such as Alzheimer's disease, pulmonary emphysema, rheumatoid arthritis, muscular dystrophy, osteoporosis, neuronal degenerative disease and cancer invasion and metastasis. Accordingly, it would be important to identify and isolate a novel cysteine proteinase, followed by elucidating the function of said cysteine proteinase involved in various diseases and disorders, especially cancers in view of not only elucidation of critical mechanism leading to such diseases and disorders but also researches and developments of therapy and therapeutic drugs thereagainst.
The present inventors have taken a view that, in the cysteine proteinase family, there will be novel members which have not been reported yet. The present inventors have carried out various studies by means of genetic engineering techniques. As a result, they have succeeded in cloning a human gene coding for a novel cysteine proteinase member and have disclosed all of its gene nucleotide sequence and amino acid sequence whereupon the present invention has been accomplished. When the putative amino acid sequence of the isolated novel cysteine proteinase was compared with the sequences of the already-reported cathepsins, it was noted that it has 78% homology to cathepsin L and not more than 40% homology to other cathepsins, respectively. From this characteristic feature in the amino acid sequence, said novel member was named “cathepsin L2”.
Accordingly, the present invention provides novel proteins having cathepsin L2 activity, of which origin is human, in particular, polypeptides (or proteins) called “cathepsin L2” herein, processes for producing the same and use thereof, genes (or polynucleotides or nucleic acids) coding for said proteins, applications thereof, etc.
The present invention provides probes for hybridization, specific to cathepsin L2 genes. Further, the present invention provides antib
Campo Elías
Cazorla Maite
Fueyo Antonio
López-Otín Carlos
Santamaría Inigo
Daiichi Fine Chemical Co., Ltd.
Prouty Rebecca E.
Wenderoth , Lind & Ponack, L.L.P.
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