Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Patent
1994-12-01
1999-04-06
LeGuyader, John L.
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
435 6, 435 911, 4351723, 435325, 435372, 435375, 536 231, 536 2431, 536 245, 514 44, C07H 2104, C12Q 168
Patent
active
058917250
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/00911, filed Apr. 15, 1993.
BACKGROUND OF THE INVENTION
The BCHE and ACHE genes encoding the acetylcholine hydrolyzing enzymes butyrylcholinesterase (BuChE, EC 3.1.1.8) and actylcholinesterase (AChE, EC 3.1.1.7) are expressed in various developing cell types, including Neuron 1:165-173 (1988); Malinger, G., et al., Mol. Neurosci. 1:77-84 (1989)!.
Both AChE and BuChE include the peptide motif S/T-P-X-Z, which makes-them potential substrates for phosphorylation by cdc2 kinases, the general Acad. Sci., USA 89: 579-583 (1992)!. Most other substrates of cdc2 kinases perform biological functions necessary for cell cycle-related processes with either CHE or cdc2 transcription processes may be expected to divert and/or arrest cell division, and controlling these processes can be useful for several, medically important, procedures.
Biochemical and histochemical analyses indicate that both AChE and BuChE are expressed, in high levels, in various fetal tissues of multiple 12:335-378, Harris, J. R., Ed., Plenum Press, N.Y. (1988)!, where cholinesterases (ChEs) are coordinately regulated with respect to cell 49:175-182 (1987)!. The specific role to be attributed to ChEs in embryonic development may hence be related with cell division, so that their biological function(s) in these tissues are tentatively implicated in the control of organogenesis.
In addition to its presence in the membranes of mature erythrocytes, AChE al., J. Cell Physiol. 103:201-208 (1980)! and its activity serves as an ibid.!. Furthermore, administration of acetyl- choline analogues as well as cholinesterase inhibitors has been shown to induce megakaryocytopoiesis Haematol. 12:3-27 (1983)!, implicating this enzyme in the commitment and development of these haematopoietic cells. al., Proc. Natl. Acad. Sci., USA 86:3555-3559 (1987); Soreq et al., Proc. Natl. Acad. Sci., USA 87:9688-9692 (1990)! and the human CHEl locus has 3q26-ter chromosomal domain that is subject to aberrations in leukemias T., et al., Cancer 55:535-541 (1985)!. Co-amplification of the ACHE and BCHE genes was subsequently observed in leukemias and platelet disorders Zakut, H., et al., Mutation Research, in press (1992)!. The hemopoietic system thus appears to be subject to developmental control as affected by the expression of the ChEs.
Inhibition of the expression of developmentally important genes should, in principle, divert developmental processes to directions which are not dependent on the expression of these genes. One useful approach to affect such developmental processes is based on "antisense" technology. The use of oligonucleotides to intervene in the genetic processes of the cell bears an important therapeutic potential. Thus, "informational drugs" with possible clinical applications are being developed which arrest the expression of cloned genes. The hematopoietic system may be the first logical target for novel therapy protocols based on the recent achievement in genetic engineering, since it includes proliferating stem cells and al., Harrison's Principles of Internal Medicine, 12th Ed., McGraw-Hill, Inc., New York, Chapters 268-269; 285-288 (1991)!. Stem cells may be defined as cells which can replicate repeatedly and differentiate into various kinds of committed cells. Commitment will gradually limit the differentiation choices for cells in which it occurs, until precursor cells are formed with only one choice (i.e. erythrocytes, megakaryocytes or macrophages). The first stem cells can thus be defined as totipotent, i.e. they may make all of the choices in the blood and immune system. The orientation of such cells into desired direction should be most useful in overcoming undesired changes, such as depletion or excess of specific subpopulations of hemopoietic cells. Less, although also useful is the redirection of the more limited pluripotent stem cells. Stem cells account for .ltoreq.0.1% of cells in bone marrow. They can be detected either directly, by immunocytochemical methods, or retroactively, by cell culture growth an
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W
Eckstein Fritz
Soreq Hermona
Zakut Haim
LeGuyader John L.
Yissum Research Development Co. of the Hebrew Univ. of Jerusalem
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