Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-04-14
2003-11-04
Carlson, Karen Cochrane (Department: 1653)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S226000, C435S325000, C435S219000, C435S455000
Reexamination Certificate
active
06642368
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is generally in the field of molecular biology. This invention relates to the control of programmed cell death.
2. Related Art
Programmed Cell Death
Apoptosis, also referred to as programmed cell death or regulated cell death, is a process by which organisms eliminate unwanted cells. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis, such as in tissue remodeling and the establishment of immune self-tolerance, during aging and in disease (Raff, M. C.,
Nature
356:397-400 (1992); Glucksmann, A.,
Biol. Rev. Cambridge Philos. Soc.
26:59-86 (1950); Ellis et al.,
Dev.
112:591-603 (1991); Vaux et al.,
Cell
76:777-779 (1994); Thompson, C. B.,
Science
267:1456-1462 (1995)). Programmed cell death can also act to regulate cell number, to facilitate morphogenesis, to remove harmful or otherwise abnormal cells and to eliminate cells that have already performed their function. Additionally, programmed cell death is believed to occur in response to various physiological stresses such as hypoxia or ischemia. The morphological characteristics of apoptosis include plasma membrane blebbing, condensation of nucleoplasm and cytoplasm and degradation of chromosomal DNA at inter-nucleosomal intervals. (Wyllie, A. H., in
Cell Death in Biology and Pathology
, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34).
Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. H., in
Cell Death in Biology and Pathology
, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34) and occurs when a cell activates its internally encoded suicide program as a result of either internal or external signals. The suicide program is executed through the activation of a carefully regulated genetic program (Wylie, A. H., et al.,
Int. Rev. Cyt.
68: 251 (1980); Ellis, R. E., et al.,
Ann. Rev. Cell Bio.
7: 663 (1991); Yuan, Y.
Curr. Op. Cell. Biol.
7:211-214 (1995)). In many cases, gene expression appears to be required for apoptosis, since cell death can be prevented by inhibitors of RNA or protein synthesis (Cohen et al.,
J. Immunol.
32:38-42 (1984); Stanisic et al.,
Invest. Urol.
16:19-22 (1978); Martin et al.,
J. Cell Biol.
106:829-844 (1988).
Acute and chronic disregulation of cell death is believed to lead to a number of major human diseases (Barr et al.
Biotech.
12:487-493 (1995); Thompson C. B.,
Science
267:14561462 (1995)). These diseases include but are not limited to malignant and pre-malignant conditions, neurological and neurodegenerative disorders, heart disease, immune system disorders, intestinal disorders, kidney disease, aging, viral infections and AIDS.
Malignant and pre-malignant conditions may include solid tumors, B cell lymphomas, chronic lymphocytic leukemia, prostate hypertrophy, preneoplastic liver foci and resistance to chemotherapy. Neurological disorders may include stroke, Alzheimer's disease, amyotrophic lateral sclerosis, prion-associated disorder and ataxia telangiectasia. Heart disease may include ischemic cardiac damage and chemotherapy-induced myocardial damage. Immune system disorders may include AIDS, type I diabetes, lupus erythematosus, Sjogren's syndrome and glomerulonephritis. Intestinal disorder may include dysentery, inflammatory bowel disease and radiation- and HIV-induced diarrhea. Kidney disease may include polycystic kidney disease and anemia/erythropoiesis. Specific references to many of these pathophysiological conditions as involving disregulated apoptosis can be found in Barr et al. Id.-Table I.
Caspases
Caspases are a family of proteins, previously referred to as ICE or ced-3 proteins, involved in the regulation of apoptosis. A genetic pathway of programmed cell death has been identified in the nematode
Caenorhabditis elegans
(Ellis, R. E., et al.,
Annual Review of Cell Biology
7:663-698 (1991).) In this genetic pathway, the genes ced-3 and ced-4 are required for cell death, while another gene, ced-9, is a negative regulator of cell death. The ced-3 gene encodes a cysteine protease (Yuan, J., et al.,
Cell
75:641-652 (1993)) which shares sequence similarity to the mammalian interleukin-1&bgr;-converting enzyme (ICE), also called caspase-1, which catalyzes the processing of pro-interleukin-1&bgr; to its biologically active form (Thornberry, N. A., et al.,
Nature
356:768-774 (1992)). The active centers of ICE and Ced-3 are remarkably conserved with an identical pentapeptide QACRG (SEQ ID NO:3) in which the cysteine is the catalytic residue (Yuan, J., et al.,
Cell
75:641-652 (1993); Thornberry, N. A., et al.,
Nature
356:768-774 (1992)). ICE and Ced-3 exhibit unique requirement for Asp at P1 position for cleavage with different preference for P2-P4 positions in their substrates (Thornberry, N. A., et al.,
Nature
356:768-774 (1992); Xue, D., et al.,
Genes and Development
10:1073-1083 (1996)). The ICE/Ced-3 family of cysteine proteases have recently been renamed as caspases (Alnemri, E. S., et al.,
Cell
87:171 (1996)), which stands for cysteine aspartic acid specific proteases. There have been at least ten human caspases identified (Stennicke, H. R. and Salvesen, G. S., J. Biol. Chem. 272(41):25719-25723 (1997)).
Overexpression of ICE in a rat fibroblast cell line results in apoptosis, which can be blocked by mammalian Bcl-2, a homolog of the nematode cell death suppressor, Ced-9 (Miura, M., et al.,
Cell
75:653-660 (1993)). While Ced-3 is the only caspase identified in
C. elegans
, at least twelve caspases have been identified in mammals (Kumar, S., et al.,
Genes and Development
8:1613-1626 (1994); Wang, L., et al.,
Cell
78:739-750 (1994); Femandez-Alnemri, T., et al.,
J. Biol. Chem.
269:30761-30764 (1994); Tewari, M.,
Cell
81:801-809 (1995); Faucheu, C., et al.,
The EMBO Journal
14:1914-1922 (1995); Munday, N. A., et al.,
J. Biol. Chem.
270:15870-15876 (1995); Duan, H., et al.,
J. Biol. Chem.
271:1621-1625 (1996); Wang, S., et al.,
J. Biol. Chem.
271:20580-20587(1996); Van de Craen, M., et al.,
FEBS Letters
403:61-69 (1997)).
The members of the caspase family are expressed in multiple tissues and cell types during development and adult life. Thus, unlike that in
C. elegans
where a single ced-3 gene controls all programmed cell death, multiple homologs of CED-3 regulate mammalian apoptosis. Interesting results have come from gene knockout experiments where mice that are mutant for ICE and caspase-3 have been generated (Li, P., et al.,
Cell
80:401-411 (1995); Kuida, K., et al.,
Science
267:2000-2003 (1995); Kuida, K., et al.,
Nature
384:368-372 (1996)). The results emerging from analyses of these mutant mice support the hypothesis that these homologs act in both parallel and sequential fashion to regulate apoptosis (Enari, M., et al.,
Nature
380:723-725 (1996)). Ice−/− embryonic fibroblasts and B lymphoblasts are resistant to granzyme B-induced apoptosis (Shi, L., et al.,
Proc. Natl. Acad. Sci. US A
93:11002-11007 (1996)). Caspase-3−/− mutant mice are defective in brain development, exhibiting a variety of hyperplasias and disorganizations which may be due to the absence of apoptosis, although their thymocytes respond normally to a variety of apoptotic agents (Kuida, K., et al.,
Nature
384:368-372 (1996)). These results suggest that either ICE or caspase-3 is critical for certain types of apoptosis in certain cells while their functions in other cell types are redundant.
Inhibitors of the caspase family prevent apoptosis induced by a variety of signals such as trophic factor deprivation, Fas and TNF, suggesting that the members of the caspase family are critical regulators of mammalian apoptosis (Miura, M., et al.,
Cell
75:653-660 (1993); Gagliardini, V., et al.,
Science
263:97-100 (1994); Tewari, M., and Dixit, V. M.,
J. Biol. Chem.
270:3255-3260 (1995)). Since cells have been found to express multiple caspases (Wang, L., et al.,
Cell
78:739-750 (1994)), it is proposed that caspases may act in a proteolytic
Morishima Nobuhiro
Yuan Junying
Carlson Karen Cochrane
Robinson Hope A.
Sterne Kessler Goldstein & Fox P.L.L.C.
The General Hospital Corporation
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