Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-07-02
2004-05-11
Chan, Christina (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S070210, C530S350000, C530S387100, C530S387300, C530S388150, C530S388260, C530S389100, C530S391300
Reexamination Certificate
active
06733981
ABSTRACT:
This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptides of the present invention are interlude-1&bgr; converting enzyme like apoptosis protease-3 and interlude-1&bgr; converting enzyme like apoptosis protease-4, sometimes hereinafter referred to collectively as “ICE-LAP-3 and 4”. The invention also relates to inhibiting the action of such polypeptides.
It has recently been discovered that an interlude-1&bgr; converting enzyme (ICE) is responsible for cleaving pro-IL-1&bgr; into mature and active IL-1&bgr; and is also responsible for programmed cell death (or apoptosis), which is a process through which organisms get rid of unwanted cells. The present invention is directed to ICE-LAP-3 and 4 which are structurally related to ICE.
In the nematode
caenorhabditis elegans
, a genetic pathway of programmed cell death has been identified (Ellis, R. E., et al. Annu. Rev. Cell Biol., 7:663-698 (1991)). Two genes, ced-3 and ced-4, are essential for cells to undergo programmed cell death in
C. elegans
(Ellis, H. M., and Horvitz, H. R., Cell, 44:817-829 (1986)). Recessive mutations that eliminate the function of these two genes prevent normal programmed cell death during the development of
C. elegans
. The known vertebrate counterpart to ced-3 protein is ICE. The overall amino acid identity between ced-3 and ICE is 28%, with a region of 115 amino acids (residues 246-360 of ced-3 and 164-278 of ICE) that shows the highest identity (43%). This region contains a conserved pentapeptide, QACRG (residues 356-360 of ced-3), which contains a cysteine known to be essential for ICE function. The ICE-LAP-3 and 4 polypeptides of the present invention also have the same conserved pentapeptide and the cysteine residue which is essential for ICE function.
The similarity between ced-3 and ICE suggests not only that ced-3 might function as a cysteine protease but also that ICE might act as a vertebrate programmed cell death gene. ced-3 and the vertebrate counterpart, ICE, control programmed cell death during embryonic development, (Gagliarnini, V. et al., Science, 263:826:828 (1994).
ICE mRNA has been detected in a variety of tissues, including peripheral blood monocytes, peripheral blood lymphocytes, peripheral blood neutrophils, resting and activated peripheral blood T lymphocytes, placenta, the B lymphoblastoid line CB23, and monocytic leukemia cell line THP-1 cells (Cerretti, D. P., et al., Science, 256:97-100 (1992)), suggesting that ICE may have an additional substrate in addition to pro-IL-1&bgr;. The substrate that ICE acts upon to cause cell death is presently unknown. One possibility is that it may be a vertebrate homolog of the
C. elegans
cell death gene ced-4. Alternatively, ICE might directly cause cell death by proteolytically cleaving proteins that are essential for cell viability.
The mammalian gene bc1-2, has been found to protect immune cells called lymphocytes from cell suicide. Also, crmA, a cow pox virus gene protein product inhibits ICE's protein splitting activity.
The polypeptides of the present invention have been putatively identified as ICE-LAP-3 and 4. This identification has been made as a result of amino acid sequence homology.
In accordance with one aspect of the present invention, there are provided novel mature polypeptides which are ICE-LAP-3 and 4, as well as fragments, analogs and derivatives thereof. The polypeptides of the present invention are of human origin.
In accordance with another aspect of the present invention, there are provided polynucleotides (DNA or RNA) which encode such polypeptides.
In accordance with yet a further aspect of the present invention, there is provided a process for producing such polypeptides by recombinant techniques.
In accordance with yet a further aspect of the present invention, there is provided a process for utilizing such polypeptides, or polynucleotides encoding such polypeptides for therapeutic purposes, for example, as an antiviral agent, an anti-tumor agent and to control embryonic development and tissue homeostasis.
In accordance with yet a further aspect of the present invention, there is provided an antibody against such polypeptides.
In accordance with yet another aspect of the present invention, there are provided antagonists to such polypeptides, which may be used to inhibit the action of such polypeptides, for example, in the treatment of Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, septic shock and head injuries.
These and other aspects of the present invention should be apparent to those skilled in the art from the teachings herein.
The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
FIGS. 1A-B
show the cDNA (SEQ ID NO:1) and corresponding deduced amino acid sequence (SEQ ID NO:2) of ICE-LAP-3. The polypeptide encoded by the amino acid sequence shown is the putative mature form of the polypeptide (minus the initial methionine residue), and the standard one-letter abbreviation for amino acids is used.
FIGS. 2A-B
show the cDNA (SEQ ID NQ:3) and corresponding deduced amino acid sequence (SEQ ID NQ:4) of ICE-LAP-4. The polypeptide encoded by the amino acid sequence shown is the putative mature form of the polypeptide (minus the initial methionine residue).
FIGS. 3A-C
show an amino acid sequence comparison between ICE-LAP-3, ICE-LAP-4, human ICE (SEQ ID NO:14) and the
C. elegan
cell death gene ced-3 (SEQ ID NO:13). Shaded areas represent amino acid matches between the
Sequencing inaccuracies are a common problem when attempting to determine polynucleotide sequences. Accordingly, the sequences of
FIGS. 1A-B
and
2
A-B are based on several sequencing runs and the sequencing accuracy is considered to be at least 97%.
In accordance with an aspect of the present invention, there are provided isolated nucleic acids (polynucleotides) which encode the mature polypeptides having the deduced amino acid sequence of
FIGS. 1A-B
and
2
A-B or for the mature polypeptide encoded by the cDNA of the clones deposited as ATCC Deposit No. 75875 encoding ICE-LAP-3, and ATCC Deposit No. 75873 encoding ICE-LAP-4, which were deposited Aug. 25, 1994.
These deposits are biological deposits with the American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209. Since the strains referred to are being maintained under the terms of the Budapest Treaty, they will be made available to a patent office signatory to the Budapest Treaty.
The polynucleotide encoding ICE-LAP-3 can be detected from human prostate, human endometrial tumor, human pancreatic tumor, human adrenal gland tumor and human tonsil. The full-length encoding ICE-LAP-3 was different sequences. discovered in a cDNA library derived from human endometrial tumor. It is structurally related to the Interlude-1 converting enzyme family. It contains an open reading frame encoding a protein of approximately 341 amino acid residues. The protein exhibits the highest degree of homology to
C. elegans
cell death gene ced-3 which is a homolog of human interlude-1 converting enzyme, with 68% similarity and 43% identity over the entire amino acid sequence. It should be pointed out that the pentapeptide QACRG is conserved and is located at amino acid position 184-188.
The polynucleotide encoding ICE-LAP-4 was discovered in a cDNA library derived from human tonsils. It is structurally related to the ICE family. It contains an open reading frame encoding a protein of about 277 amino acid residues. The protein exhibits the highest degree of homology to the
C. elegans
cell death gene ced-3 with 29% identity and 46% similarity over a 277 amino acid stretch. It is also important that the pentapeptide QACRG is conserved and is located at amino position 161-165.
The polynucleotides of the present invention may be in the form of R
Hastings Gregg A.
He Wei Wu
Hudson Peter L.
Rosen Craig A.
Chan Christina
Human Genome Sciences Inc.
Human Genome Sciences Inc.
Huynh Phuong
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