Drug – bio-affecting and body treating compositions – Miscellaneous
Reexamination Certificate
1999-06-08
2002-08-27
Prouty, Rebecca E. (Department: 1652)
Drug, bio-affecting and body treating compositions
Miscellaneous
C424S610000, C514S211070, C514S410000, C514S183000, C435S015000
Reexamination Certificate
active
06441053
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is protein kinase enzymes involved in glycogen metabolism, in signal transduction, and in cellular regulation of enzyme activity and transcription.
BACKGROUND OF THE INVENTION
Lithium is an effective drug for the treatment of bipolar (manic-depressive) disorder (Price et al., 1994, New Eng. J. Med. 331:591-598; Goodwin et al., 1990, In: Manic-Depressive Illness, New York: Oxford University Press). Lithium is not only effective for treatment of acute episodes of mania, but this compound also reduces the frequency and severity of recurrent episodes of mania and depression in patients with bipolar and unipolar disorders (Goodwin, et al., 1990, supra). Lithium can be used to treat profound depression in some cases. Despite the remarkable efficacy of lithium observed during decades of its use, the molecular mechanism(s) underlying its therapeutic actions have not been fully elucidated (Bunney, et al., 1987, In: Psychopharmacology: The Third Generation of Progress, Hy, ed., New York, Raven Press, 553-565; Jope et al., 1994, Biochem. Pharmacol. 47:429-441; Risby et al., 1991, Arch. Gen. Psychiatry 48:513-524; Wood et al., 1987, Psychol. Med. 17:570-600).
Lithium does not have an immediate effect during the treatment of mania, but rather requires several weeks to manifest a clinical response. It has been suggested that this delay reflects changes in the expression of genes involved in alleviation of mania (Manji et al., 1995, Arch. Gen. Psychiatry 52:531-543).
In addition to its use as a therapeutic drug for the treatment of mania, lithium exhibits numerous physiological effects in animals. For example, lithium mimics insulin action by stimulating glycogen synthesis (Bosch et al., 1986, J. Biol. Chem. 261:16927-16931). Further, exposure to lithium has dramatic morphogenic effects during the early development of numerous organisms. The effects of lithium on the development of diverse organisms, including Dictyostelium, sea urchins, zebrafish, and Xenopus have been reported (Maeda, 1970, Dev. Growth & Differ. 12:217-227; Van Lookeren Campagne et al., 1988, Dev. Genet. 9:589-596; Kao et al., 1986, Nature 322:371-373; Stachel et al., 1993, Development 117:1261-1274; Livingston et al., 1989. Proc. Natl. Acad. Sci. U.S.A. 86:3669-3673).
In Dictyostelium discoideum
, lithium alters cell fate by blocking spore cell development and promoting stalk cell development (Maeda, 1970, supra; Van Lookeren Campagne et al., 1988, supra). In Xenopus, lithium induces an expansion of dorsal mesoderm, leading to duplication of the dorsal axis or, in extreme cases, entirely dorsalized embryos which lack identifiably ventral tissues (Kao et al., 1986, Nature 322:371-373). Lithium also rescues UV-ventralized embryos (Kao et al., 1986, supra). In addition, treatment of sea urchin animal blastomeres with lithium induces the blastomeres to display a morphology resembling that of isolated vegetal blastomeres (Horstadius, 1973, In: Experimental Embryology of Echinoderms, Oxford University Press, Oxford).
Even though lithium is remarkably effective for the treatment of mania in many human patients, lithium treatment in humans is accompanied by several serious drawbacks (Baraban, 1994, Proc. Natl. Acad. Sci. U.S.A. 91:5738-5739). Particularly troublesome is the slim margin between therapeutic and toxic levels of lithium in vivo. Furthermore, because clearance of lithium is intimately tied to sodium and water excretion, a slight change in electrolyte balance can precipitate a life-threatening increase in lithium levels in vivo (Baraban, supra). In addition, even tight regulation of lithium within its therapeutic window is associated with a wide range of side effects, such as tremor, renal dysfunction, thyroid abnormalities, and birth defects (Jefferson et al., 1989, In: Comprehensive Textbook of Psychiatry, Kaplan et al., eds., Williams & Wilkins, Baltimore, vol. 2, 1655-1662). It is recommended that facilities for prompt and accurate serum lithium determinations be available before administering lithium to a patient (Physicians Desk Reference, 51 st Ed., 1997, p. 2658). In addition, lithium should generally not be administered to patients having significant renal or cardiovascular disease, severe debilitation or dehydration, sodium depletion, or to patients receiving diuretics, since the risk of lithium toxicity is very high in such patients (Physicians Desk Reference, 1997, supra, at 2352). Numerous other side effects are detailed in the Physicians Desk Reference (1997, supra, at 2352, 2658).
The mechanism or mechanisms by which lithium exerts these diverse effects are unclear (Price et al., 1994, New Eng. J. Med. 331:591-598; Goodwin et al., 1990, In: Manic-Depressive Illness, New York, Oxford University Press; Berridge et al., 1989, Cell 59:411-419; Avissar et al., 1988, Nature 331:440-442). A favored hypothesis, the inositol depletion hypothesis, is based on the observation that lithium inhibits inositol monophosphatase (IMPase) and, by doing so, depletes cells of endogenous inositol (Berridge et al., 1989, Cell 59:411-419; Hallcher et al., 1980, J. Biol. Chem. 255:10896-10901). Cells that do not have an exogenous source of inositol would, in principle, be unable to synthesize phosphatidyl-3-inositol phosphate, the precursor of inositol 1,4,5 tris-phosphate (IP
3
). Thus, according to the inositol depletion hypothesis, lithium-treated cells are unable to generate IP
3
in response to extracellular signals and, as a consequence, IP
3
-dependent responses are blocked. Some experimental results appear to support the inositol depletion hypothesis (Baraban, 1994, Proc. Natl. Acad. Sci. U.S.A. 91:5738-5739; Berridge et al., 1989, Cell 59:411-419; Manji et al., 1995, Arch. Gen. Psychiatry 52:531-543; Busa et al., 1989, Dev. Biol. 132:315-324). However, other experimental results do not support this hypothesis (Klein et al., 1996, Proc. Natl. Acad. Sci. U.S.A., 93:8455-8459; Drayer et al., 1994, EMBO J. 13:1601-1609).
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase having a 47 kDa monomeric structure. It is one of several protein kinases which phosphorylates glycogen synthase (Embi, et al., 1980, Eur. J. Biochem., 107:519-527; Hemmings et al., 1982, Eur. J. Biochem. 119:443-451). GSK-3 is also referred to in the literature as factor A (F
A
) in the context of its ability to phosphorylate F
C
, a protein phosphatase (Vandenheede et al., 1980, J. Biol. Chem. 255:11768-11774). Other names for GSK-3 and homologs thereof include zeste-white3/shaggy (zw3/sgg; the
Drosophila melanogaster
homolog), ATP-citrate lyase kinase (ACLK or MFPK; Ramakrishna et al., 1989, Biochem. 28:856-860; Ramakrishna et al., 1985, J. Biol. Chem. 260:12280-12286), GSLA (the Dictyostelium homolog; Harwood et al., 1995, Cell 80:139-48), and MDSI, MCK1, and others (yeast homologs; Hunter et al., 1997, TIBS 22:18-22).
The gene encoding GSK-3 is highly conserved across diverse phyla. GSK-3 exists in two isoforms in vertebrates, GSK-3&agr; and GSK-3&bgr;. In vertebrates, the amino acid identity among homologs is in excess of 98% within the catalytic domain of GSK-3 (Plyte et al., 1992, Biochim. Biophys. Acta 1114:147-162). It has been reported that there is only one form of GSK-3 in invertebrates, which appears to more closely resemble GSK-3&bgr; than GSK-3&agr;. Amino acid similarities (allowing for conservative replacements) between the slime mold and fission yeast proteins with the catalytic domain of human GSK-3&bgr; are 81% and 78%, respectively (Plyte et al., 1992, supra). The remarkably high degree of conservation across the phylogenetic spectrum suggests a fundamental role for GSK-3 in cellular processes.
GSK-3 has been demonstrated to phosphorylate numerous proteins in vitro, including, but not limited to glycogen synthase, phosphatase inhibitor I-2, the type-II subunit of cAMP-dependent protein kinase, the G-subunit of phosphatase-1, ATP-citrate lyase, acetyl coenzyme A carboxylase, myelin basic protein, a microtubule-associated protein, a neurofilament protein, an N-CAM
Klein Peter S.
Melton Douglas
Morgan & Lewis & Bockius, LLP
Prouty Rebecca E.
The Trustees of the University of Pennsylvania
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