Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving hydrolase
Reexamination Certificate
1997-08-07
2001-04-10
Saunders, David (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving hydrolase
C424S094650, C435S375000, C514S002600, C514S012200, C514S021800, C514S054000, C530S350000
Reexamination Certificate
active
06214572
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is generally in the field of molecular biology as related to the control of programmed cell death. The invention also relates to transgenic non-human animals comprising a disrupted Ich-3 (Caspase-11) gene. This invention further relates to methods of making and using the transgenic animals.
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 and during aging (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)). 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, 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). A genetic pathway of programmed cell death was first identified in the nematode
C. elegans
(Ellis, R. E., et al.,
Annu. Rev. Cell Biol.
7:663-698 (1991)). In this pathway, the function of two genes, ced-3 and ced-4, are required for cells to undergo programmed cell death Genetic mosaic analysis indicated that both ced-3 and ced-4 most likely act in dying cells to induce cell death; thus, they are essential parts of intracellular machinery involved in execution of cell death (Yuan & Horvitz,
Dev. Biol.
138:33-41 (1990)). Furthermore, in
C. elegans,
the products of ced-3 and ced-4 genes carry out the program of cellular suicide (Yuan & Horvitz,
Dev. Bio.
138: 33 (1990)).
Amino acid sequence of CED-3 protein is homologous to mammalian interleukin-1&bgr; converting enzyme (ICE) with 28% amino acid identity (Yuan et al.,
Cell
75:641-652 (1993)). The C terminal half of the CED-3 is more homologous to ICE (43% identity), which includes the active pentapeptide QACRG present in all members of the ICE/CED-3 family.
Interleukin-1-&bgr; Converting Enzyme (ICE) Family
The interleukin-1&bgr; converting enzyme (ICE) family is a growing family of cysteine proteases involved in cytokine maturation and apoptosis (Yuan, J.,
Curr. Opin. in Cell Biology
7:211-214 (1995)). ICE is a cytoplasmic cysteine protease responsible for proteolytically processing pro-interleukin-1&bgr; (31 kDa) into active form (17 kDa) (Thornberry, N. A.,
Nature
356:768-774 (1992), Cerretti, D. P., et al.,
Science
256:97-100 (1992)). ICE is synthesized as a precursor of 45 kDa which is proteolytically cleaved during activation to generate two subunits of 22 kDa p20) and 10 kDa (p10) (Thornberry, N. A., et al.,
Nature
356:768-774 (1992)). X-ray crystallography analysis of three dimensional structure of ICE showed that ICE is a homodimer of activated ICE p20 and p10 subunits (Wilson, K. P., et al.,
Nature
370:270-275 (1994); Walker, N. P. C., et al.,
Cell
78:343-352 (1994)). Activated ICE can cleave the inactive ICE precursor; however, in vitro synthesized ICE precursor cannot cleave itself (Thornberry, N. A., et al.,
Nature
356:768-774 (1992)), suggesting that ICE may need to be activated by another protease in vivo.
The amino acid sequence of ICE shares 29% identity with
C. elegans
cell death gene product Ced-3 (Yuan et al.,
Cell
75:641-752 (1993)) which suggests that ICE may play a role in controlling mammalian apoptosis.. Expression of Ice in a number of mammalian cell lines induces apoptosis (Miura et al.,
Cell
75:653-660 (1993); Wang et al.,
Cell
87:739-750 (1994)). Microinjection of an expression vector of crmA, a cowpox virus gene encoding a serpin that is a specific inhibitor of ICE, prevents not only death of neurons from dorsal root ganglia induced by trophic factor deprivation but also the death of ciliary ganglia (Gagliardini et al.,
Science
263:826-828 (1994); Li et al.,
Cell
80:401-411 (1995); Allsopp et al.,
Cell
73:295-307, (1993)). Expression of crmA can also suppress apoptosis induced by TNF-&agr; and Fas (Enari et al.,
Nature
375:78-81 (1995); Los et al.,
Nature
375:81-83 (1995); Kuide et al.,
Science
267:2000-2002 (1995); Miura et al.,
Proc. Natl. Acad. Sci. U.S.A.
92:8318-8322 (1995)). These experiments suggest that the members of the ICE family play important roles in controlling mammalian apoptosis. These results did not indicate, however, which member of the ICE family is critical for cell death since CrmA may cross-inhibit other members of the ICE family.
The mammalian ICE/CED-3 family now includes eight members: ICE, TX/ICE
rel
II/ICH-2, ICE
rel
III, ICH-1/NEDD2, CPP32/Yama/Apopain, MCH2, MCH-3/ICE-LAP3/MCH-2 and ICH-3 (Kumar et al.,
Genes Dev.
8:1613-1626 (1994); Fernandes-Alnemri, et al.,
J. Biol. Chem.
269:30761-30764 (1994); Fernandez-Alnemri et al,
Cancer Res.
55:2737-2742 (1995); Fernandes-Alnemri et al.,
Cancer Res.
55:6045-6052 (1996); Wang et al.,
Cell
78:739-750 (1994); Faucheu, et al,
EMBO J.
14:1914-1922(1995); Tewari & Dixit,
J. Biol. Chem.
270:3255-3260 (1995); Kamens et al.,
J. Biol Chem.
270:15250-15256 (1995); Munday, N. A., et al.,
J. Biol. Chem.
270:15870-15876 (1995); Duan, H. J., et al.,
J. Biol. Chem.
271:1621-1625 (1996); Lippke, J. A., et al.,
J. Biol. Chem.
271:1825-1828 (1996)). Since ICH-3 is most homologous to TX, it may be the mouse version of human TX. This cannot be concluded at the moment, however, because TX has been shown to cleave pro-ICE (Faucheu, et al.,
EMBO J.
14:1914-1922 (1995)) whereas ICH-3 has not been shown to cleave pro-ICE in a similar assay (data not shown). The current designation of ICH-3 is Caspase-11.
Overexpression of Nedd-2/Ich-1
L
induces cell death very effectively (Kumar et al.,
Genes Dev.
8:1613-1626 (1994); Wang et al.,
Cell
87:739-750 (1994)). Expression of CPP32/Yama in full length cDNA induces apoptosis of insect Sf9 cells but not that of mammalian cells (Fernandes-Alnemri et al.,
J Biol. Chem.
269:30761-30764 (1994); E. S. Alnemri, personal communication). Recombinant CPP32/Yama is inactive and cleavage of CPP32/Yama by ICE in vitro activates the precursor (Tewari et al.,
Cell
81:801-809 (1995b)), suggesting that in vivo CPP32(Yama may be activated by another protease to induce apoptosis. Expression of MCH2&agr; also induces apoptosis of insect Sf9 cells but not that of mammalian cells (Fernandes-Alnemri et al.,
Cancer Res.
55:2737-2742 (1995)). Thus, the members of the ICE family can be classified into 2 classes: those that when overexpressed in mammalian cells can induces apoptosis (e.g. Ice and Ich-1) and those that when overexpressed in mammalian cells cannot induce apoptosis (e.g. CPP32 and Mch-2). These experimental evidence suggest that in vivo members of the ICE family may be arranged in prot
Miura Masayuki
Wang Suyue
Yuan Junying
Saunders David
Sterne Kessler Goldstein & Fox P.L.L.C.
The General Hospital Corporation
Tung Mary Beth
LandOfFree
Programmed cell death and ICH-3 does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Programmed cell death and ICH-3, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Programmed cell death and ICH-3 will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2540025