Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Nucleoproteins – e.g. – chromatin – chromosomal proteins,...
Reexamination Certificate
1999-01-19
2001-03-27
Guzo, David (Department: 1636)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Nucleoproteins, e.g., chromatin, chromosomal proteins,...
C530S350000
Reexamination Certificate
active
06207803
ABSTRACT:
This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of a human homologue of murine requiem gene, hereinafter referred to as “REQUIEM”.
BACKGROUND OF THE INVENTION
Hematopoietic stem cell proliferation, differentiation and apoptosis, are regulated by various growth factors and cytokines (Metcalf, D.,
Science
254, 529-531 (1992) and Vaux et al.,
Nature
335, 440-442 (1988)). Such cells committed to the myeloid lineage express high affinity receptors for GM-CSF1 and IL-3 (Miyajima et al.,
Blood
82,1960-1973 (1993)). Moreover, such cells develop a requirement for GM-CSF or IL-3 to survive and undergo apoptosis in response to GM-CSF or IL-3 deprivation (Williams et al.,
Nature
343, 76-79 (1990)).
Hematopoietic cells are not unique in their requirement for growth factors for survival. Throughout development, cells of all lineages require proper signals to grow and differentiate. Failure to receive these signals often results in death of the cells by apoptosis. Even in the adult organism there is constant renewal and/or maintence of cells that requires growth factors and cytokines. Inappropriate cessation of signals from these growth factors may result in apoptosis thereby causing disfunction or disease.
Several apoptotic genes appear to be conserved in multicellular organisms. For example, the ced-3 gene of
Caenorhabditis elegans
has a family of mammalian homologue cysteine protease, including interleukin-1&bgr;-converting enzyme (ICE), Ich-1, CPP32, TX, ICErelIII, and LAP3 (Yuan, et al.,
Cell
75, 641-652 (1993) and Miura, et al.,
Cell
75, 653-660 (1993); Wang, et al.,
Cell
78, 739-750 (1994), Fernandes-Alnemri, et al.,
JBC
269, 30761-30764 (1994), Faucheu, et al.,
EMBO J
14, 1914-1922 (1995), Munday, et al.,
JBC
270, 15870-15876 (1995) and Duan, et al.,
JBC
271, 35013-35035 (1996)). Antagonists of the apoptosis are also conserved, such as, for example, ced-9 of
C. elegans
and its mammalian homologue bcl-2. Molecular control of initiation is less well resolved.
Cell lines that proliferate in response to IL-3 and undergo rapid programmed cell death following IL-3 deprivation can be used for expression cloning systems. Using such a system, genes that antagonize apoptosis may be found. Murine cells have been shown to be useful for this purpose. A murine Requiem gene believed to encode a transcription factor required for apoptosis response following survival factor withdrawal from myeloid cells has been described (Gabig, et al.,
JBC
269, 29515-29519 (1994)).
The present invention provides a human homolog of the Requiem gene and polypeptides encoded therefrom (herein “REQUIEM”). The human sequence contains more 5′ sequence than the mouse requiem sequence and has a more 5′ start site which is believed to be the correct start site.
SUMMARY OF THE INVENTION
Toward these ends, and others, it is an object of the present invention to provide polypeptides, inter alia, that have been identified as novel REQUIEM by homology between the amino acid sequence set out in
FIGS. 1A
,
1
B,
1
C,
1
D and
1
E and known amino acid sequences of other proteins such as those sequences set out in FIG.
2
.
It is a further object of the invention, moreover, to provide polynucleotides that encode REQUIEM, particularly polynucleotides that encode the polypeptide herein designated REQUIEM.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprises the region encoding human REQUIEM as set forth in
FIGS. 1A
,
1
B,
1
C,
1
D and
1
E.
In accordance with this aspect of the present invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressed by the human cDNA of
FIGS. 1A
,
1
B,
1
C and
1
E encoding the polypeptide in
FIGS. 1A
,
1
B,
1
C,
1
D and
1
E.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding human REQUIEM, including mRNAs, cDNAs, genomic DNAs and, in further embodiments of this aspect of the invention, biologically, diagnostically, clinically or therapeutically useful variants, analogs or derivatives thereof, or fragments thereof, including fragments of the variants, analogs and derivatives.
Among the particularly preferred embodiments of this aspect of the invention are naturally occurring allelic variants of human REQUIEM.
It also is an object of the invention to provide REQUIEM polypeptides, particularly human REQUIEM polypeptides, that may be employed for therapeutic purposes, for example, to treat viral infection, as an anti-tumor agent and to control embryonic development and tissue homeostasis.
In accordance with this aspect of the invention there are provided novel polypeptides of human origin referred to herein as REQUIEM as well as biologically, diagnostically or therapeutically useful fragments, variants and derivatives thereof, variants and derivatives of the fragments, and analogs of the foregoing.
Among the particularly preferred embodiments of this aspect of the invention are variants of human REQUIEM encoded by naturally occurring alleles of the human REQUIEM gene.
It is another object of the invention to provide a process for producing the aforementioned polypeptides, polypeptide fragments, variant and derivatives, fragments of the variants and derivatives, and analogs of the foregoing.
In a preferred embodiment of this aspect of the invention there are provided methods for producing the aforementioned REQUIEM polypeptides comprising culturing host cells having expressibly incorporated therein an exogenously-derived human REQUIEM-encoding polynucleotide under conditions for expression of human REQUIEM in the host and then recovering the expressed polypeptide. REQUIEM may also be purified from natural sources using any of many well known techniques.
In accordance with another object the invention there are provided products, compositions, processes and methods that utilize the aforementioned polypeptides and polynucleotides for research, biological, clinical, diagnostic and therapeutic purposes, inter alia.
In accordance with certain preferred embodiments of this aspect of the invention, there are provided products, compositions and methods, inter alia, for, among other things: assessing REQUIEM expression in cells by determining REQUIEM polypeptides or REQUIEM-encoding mRNA; as an antiviral agent, an anti-tumor agent and to control embryonic development and tissue homeostasis invitro, ex vivo or in vivo by exposing cells to REQUIEM polypeptides or polynucleotides as disclosed herein; assaying genetic variation and aberrations, such as defects, in REQUIEM genes; and administering a REQUIEM polypeptide or polynucleotide to an organism to augment REQUIEM function or remediate REQUIEM dysfunction. Agonists targeted to defective cellular proliferation, including, for example, cancer cells and solid tumor cells may be used for the treatment of these diseases. Such targeting may be achieved via gene therapy of using antibody fusions. Agonists may also be used to treat follicular lymphomas, carcinomas associated with p53 mutations, autoimmune disorders, such as, for example, SLE, immune-mediated glomerulonephritis; and hormone-dependent tumors, such as, for example, breast cancer, prostate cancer and ovary cancer; and viral infections, such as, for example, herpesviruses, poxviruses and adenoviruses.
In accordance with certain preferred embodiments of this and other aspects of the invention there are provided probes that hybridize to human REQUIEM sequences.
In certain additional preferred embodiments of this aspect of the invention there are provided antibodies against REQU
Gross Mitchell S
Hurle Mark Robert
Kikly Kristine Kay
Guzo David
Hecht Elizabeth J.
King William T.
Leffers, Jr. Gerald G.
Ratner & Prestia
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