Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-03-02
2002-08-20
Brumback, Brenda (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S389100
Reexamination Certificate
active
06437097
ABSTRACT:
INTRODUCTION
BACKGROUND
Apoptosis or programmed cell death is important during embryonic development, metamorphosis, tissue renewal, hormone-induced tissue atrophy and many pathological conditions. In multi-cellular organisms, apoptosis ensures the elimination of superfluous cells including those that are generated in excess, have already completed their specific functions or are harmful to the whole organism. In reproductive tissues that are characterized by cyclic functional changes, massive cell death occurs under the control of hormonal signals. A growing body of evidence suggests that the intracellular “death program” activated during apoptosis is similar in different cell types and conserved during evolution.
Apoptosis involves two essential steps. The Bcl-2 family of proteins that consists of different anti- and pro-apoptotic members is important in the “decision” step of apoptosis. In contrast, the “execution” phase of apoptosis is mediated by the activation of caspases, cysteine proteases homologous to the
C. elegans
protease ced-3, that induce cell death via the proteolytic cleavage of substrates vital for cellular homeostasis. Bcl-2-related proteins act upstream from caspases in the cell death pathway and recent studies demonstrated that another
C. elegans
gene, ced-4, or its mammalian homolog Apaf-1 can bridge between Bcl-2/ced-9 family members and caspases.
The proto-oncogene Bcl-2 was originally isolated at the breakpoint of the t(14,18) chromosomal translocation associated with follicular B-cell lymphoma. Over-expression of Bcl-2 suppresses apoptosis induced by a variety of agents both in vitro and in vivo. Subsequent studies identified a family of Bcl-2-related proteins possessing several conserved BH (Bcl-2 homology) domains important for homo- or hetero-dimerization between family members. In addition, a C-terminal transmembrane region for membrane anchoring is also conserved in most members. Based on their differential roles in regulating apoptosis, the Bcl-2-related proteins can be separated into anti-apoptotic (Bcl-2, Bcl-xL, Mcl-1, Bcl-w and Bfl-1/A1) and pro-apoptotic members (Bax, BAD, Bak, Bik, Hrk and BID). Through hetero-dimerization, the balance between pro- and anti-apoptotic proteins presumably determines cell fate. The anti-apoptotic effect of Bcl-2 is not universal, however, because Bcl-2 over-expression is not effective in blocking Fas-mediated apoptosis and the apoptosis of auto-reactive thymocytes during negative selection. Recent identification of multiple Bcl-2-related proteins suggests that selective Bcl-2 members may act in a tissue- and dimerization-specific manner.
REFERENCES
Bcl related genes are discussed in Yin et al. (1994)
Nature
369:321-323; Chittenden et al. (1995)
EMBO J
. 14:5589-5596; and White (1996)
Genes Dev
.10:1-15.
Sequences of exemplary bcl-related genes may be accessed in Genbank. The human hrk gene has the accession no. U76376 and is described in Inohara et al. (1997)
EMBO J
. 16:1686-1694. The human bcl-w gene has the accession no. U59747 and is described in Gibson et al. (1996)
Oncogene
13:665-675. Human A1 gene has the accession no. U29680, and is described in Karsan et al. (1996)
Blood
87:3089-3096. The human Bak gene has the accession no. U23765, and is described in Chittenden et al. (1995)
Nature
374:733-736. The human Bak-2 gene has the accession no. U16812, and is described in Kiefer et al. (1995)
Nature
374:736-739. The human Bik gene has the accession no. U34584, and is described in Boyd et al. (1995)
Oncogene
11:1921-1928. The human Bfl-1 gene has the accession no. U27467, and is described in Choi et al. (1995)
Oncogene
11:1693-1698. The human bcl-2 gene has the accession no. M13995, and is described in Tsujimoto and Croce (1986)
P.N.A.S
. 83:5214-5218. The human Bax genes have the accession nos. L22475, L22474 and L22473, and are described in Oltvai et al. (1993)
Cell
74:609-619. The EBV BHRF1 gene has the accession no. A22899, and is described in WO 9311267. The human mcl-1 gene is described in Kozopas et al. (1993) P.N.A.S. 90:3516-3520, and OMIM 159552.
The EST fragment, Genbank accession no. AA103989, contains partial sequence of the 5′ end of the mouse Bok gene.
SUMMARY OF THE INVENTION
Isolated nucleotide compositions and sequences are provided for Bok genes. The provided nucleic acids include splice variants encoding long forms of the protein, as well as short forms having a truncation that deletes all or a part of the BH3 domain. The short form of Bok and other related pro-apoptotic proteins may be naturally occurring or synthetic. These short forms induce cell killing without heterodimerization with antiapoptotic proteins.
The Bok nucleic acid compositions find use in identifying homologous or related genes; in producing compositions that modulate the expression or function of its encoded protein; for gene therapy; mapping functional regions of the protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of cancer and other proliferative disorders, identification of cell type based on expression, and the like.
REFERENCES:
patent: WO 93/11267 (1993-06-01), None
Boyd, Janice M., et al., “Bik, A Novel Death-Inducing Protein Shares A Distinct Sequence Motif With Bel-2 Family Proteins And Interacts With Viral And Cellular Survival-Promoting Proteins,”Oncogene(1995) vol. 11:1921-1928.
Choi, Sun Shim, et al., “A Novel Bel-2 Related Gene, Bfl-1, Is Expressed In Stomach Cancer And Preferentially Expressed In Bone Marrow,”Oncogene(1995) vol. 11:1693-1698.
Chittenden, Thomas, et al., “Induction Of Apoptosis By The Bcl-2 Homologue Bak,”Nature(Apr. 1995) vol. 374:733-736.
Chittenden, Thomas, et al., “A Conserved Domain in Bak, Distinct From BH1 And BH2, Mediates Cell Death And Protein Binding Functions,”The EMBO Journal(1995) vol. 14, No. (22):5589-5596.
Gibson, Leonie, et al., “Bcl-w, A Novel Number Of The Bcl-2 Family, Promotes Cell Survival,”Oncogene(1996) vol. 13:665-675.
Hsu, Sheau Yu et al. (Nov. 1997), “Bok is a Pro-Apoptotic Bcl-2 Protein with Restricted Expression in Reproductive Tissues and Heterodimerizes with Selective Anti-Apoptotic Bcl-2 Family Members,”Proc. Natl. Acad. Sci. USA, vol. 94:12401-12406.
Inohara, Naohiro, et al., “Harakiri, A Novel Regulator Of Cell Death, Encodes A Protein That Activates Apoptosis And Interacts Selectively With Survival-Promoting Proteins Bcl-2 And Bcl-XL,”The EMBO Journal(1997) vol. 16, No. (7):1686-1694.
Karsan, Aly, et al., “Cloning Of A Human Bcl-2 Homologue: Inflammatory Cytokines Induce Human A1 In Cultured Endothelial Cells,”Blood(Apr. 15, 1996) vol. 87, No. (8):3089-3096.
Kiefer, Michael C., et al., “Modulation Of Apoptosi By The Widely Distributed Bcl-2 Homologue Bak,”Nature(Apr. 1995) vol. 374:736-739.
Kozopas, Karen M., et al., “MCL1, A Gene Expressed In Programmed Myeloid Differentiation, Has Sequence Similarity to BCL2,”Proc. Natl. Acad. Sci. USA(Apr. 1993) vol. 90:3516-3520.
Simonian, Philip et al. (Sep. 13, 1996), “Bax Can Antagonize Bcl-XLDuring Etoposide and Cisplatin-Induces Cell Death Independently of Its Heterodimerization with Bcl-XL”,The Journal of Biological Chemistry, vol. 271(37):22764-22772.
Tsujimoto, Yoshihide, et al., “Analysis Of The Structure, Transcripts, And Protein Products Of Bcl-2, The Gene Involved In Human Follicular Lymphoma,”Proc. Natl. Acad. Sci. USA(Jul. 1986) vol. 83:5214-5218.
White, Eileen, “Life, Death, And The Pursuit Of Apoptosis,”Genes&Development(1996) vol. 10:1-15.
Yin, Xiao-Ming, et al., “BH1 and BH2 Domains Of Bcl-2 Are Required For Inhibition Of Apoptosis And Heterodimerization With Bax,”Nature(May 1994) vol. 369:321-323.
GenBank Accession No. L22475, Oltvai et al., Cell 74:609-619, 1993.
GenBank Accession No. L22474, Oltavai et al., Cell 74:609-619, 1993.
GenBank Accession No. L22473, Oltvai et al., Cell 74:609-619, 1993.
GenBank Accession No. U76376, Inohara et al., EMBO J. 16:1686-1694, 1997.
GenBank Accession No. U59747, Gibson et al., Oncogene 13:665-6
Hsu Sheau Yu
Hsueh Aaron J. W.
Bozicevic Field & Francis LLP
Brumback Brenda
Sherwood Pamela J.
The Board of Trustees of the Leland Stanford Junior University
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