Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-09-21
2004-12-14
Kemmerer, Elizabeth (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C435S252300, C435S320100, C435S325000, C530S300000, C530S350000, C536S023100
Reexamination Certificate
active
06830882
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the modulation of nuclear receptor mediated processes. In a particular aspect, the present invention relates to the use of a specific class of compounds for the modulation of processes mediated by peroxisome proliferator activated receptor-gamma (PPAR-&ggr;). In another aspect, the present invention relates to methods of testing compounds for their ability to regulate transcription-activating effects of PPAR-&ggr;.
BACKGROUND OF THE INVENTION
Peroxisome proliferators are a structurally diverse group of compounds which, when administered to rodents, elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the &bgr;-oxidation cycle (Lazarow and Fujiki,
Ann. Rev. Cell Biol
. 1:489-530 (1985); Vamecq and Draye,
Essays Biochem
. 24:1115-225 (1989); and Nelali et al.,
Cancer Res
. 48:5316-5324 (1988)). Chemicals included in this group are the fibrate class of hypolipidermic drugs, herbicides, and phthalate plasticizers (Reddy and Lalwani,
Crit. Rev. Toxicol
. 12:1-58 (1983)). Peroxisome proliferation can also be elicited by dietary or physiological factors such as a high-fat diet and cold acclimatization.
Insight into the mechanism whereby peroxisome proliferators exert their pieiotropic effects was provided by the identification of a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green,
Nature
347-645-650 (1990)). This receptor, termed peroxisome proliferator activated receptor alpha (PPAR&agr;), was subsequently shown to be activated by a variety of medium and long-chain fatty acids and to stimulate expression of the genes encoding rat acyl-CoA oxidase and hydratase-dehydrogenase (enzymes required for peroxisomal &bgr;-oxidation), as well as rabbit cytochrome P450 4A6, a fatty acid &ohgr;-hydroxylase (Gottlicher et al.,
Proc. Natl. Acad. Sci. USA
89:4653-4657 (1992); Tugwood et al.,
EMBO J
. 11:433-439 (1992) Bardot et al.,
Biochem. Biophys. Res. Comm
. 192:37-45 (1993); Muerhoff et al.,
J. Biol. Chem
. 267:19051-19053 (1992); and Marcus et al.,
Proc. Natl. Acad. Sci. USA
90(12):5723-5727 (1993).
The above-noted references suggest a physiological role for PPAR&agr; in the regulation of lipid metabolism. PPAR&agr; activates transcription by binding to DNA sequence elements, termed peroxisome proliferator response elements (PPRE), as a heterodimer with the retinoid X receptor. The retinoid X receptor is activated by 9-cis retinoic acid (see Kliewer et al.,
Nature
358:771-774 (1992), Gearing et al.,
Proc. Natl. Acad. Sci. USA
90:1440-1444 (1993), Keller et al.,
Proc. Natl. Acad. Sci. USA
90:2160-2164 (1993), Heyman et al.,
Cell
68:397-406 (1992), and Levin et al.,
Nature
355:359-361 (1992)). Since the PPAR&agr;-RXR complex can be activated by peroxisome proliferators and/or 9-cis retinoic acid, the retinoid and fatty acid signaling pathways are seen to converge in modulating lipid metabolism.
Since the discovery of PPAR&agr;, additional isoforms of PPAR have been identified, e.g., PPAR&bgr;, PPAR&ggr;and PPAR&dgr;, which are spatially differentially expressed. Because there are several isoforms of PPAR, it would be desirable to identify compounds which are capable of selectively interacting with only one of the PPAR isoforms. Such compounds would find a wide variety of uses, such as, for example, in the prevention of obesity, for the treatment of diabetes, and the like.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have identified a class of compounds which are capable of selectively modulating processes mediated by peroxisome proliferator activated receptor-gamma (PPAR-&ggr;). The identification of such compounds makes possible the selective intervention in PPAR-&ggr; mediated pathways, without exerting inadvertent effects on pathways mediated by other PPAR isoforms.
REFERENCES:
patent: 5702914 (1997-12-01), Evans et al.
patent: 5861274 (1999-01-01), Evans et al.
patent: 5939442 (1999-08-01), Evans et al.
patent: 6200802 (2001-03-01), Greene et al.
Ikonen et al. Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation. Endocrinology 135(4): 1359-1366, 1994.*
Braselmann et al. A selective transcriptional induction system for mammalian cells based on Gal4-estrogen receptor fusion proteins. Proc Natl Acad Sci U S A. 90(5):1657-1661, 1993.*
Allenby et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 90(1):30-34, 1993.*
Lehmann et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 270(22):12953-12956, 1995.*
Harmon et al. Activation of mammalian retinoid X receptors by the insect growth regulator methoprene. Proc Natl Acad Sci U S A. 92(13):6157-6160, 1995.*
Forman et al. Nuclear Hormone Receptors Activate Direct, Inverted, and Everted Repeats. Annals NY Acad Sci 761: 29-37, 1995.*
Zhang et al. Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor-gamma. J Biol Chem 271(50): 31771-31774, 1996.*
Tontonoz et al. Regulation of adipocyte gene expression and differentiation by perixosome proliferator activated receptor- gamma. Curr Opin Genet Develop 5: 571-576, 1995.*
Kliewer et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91: 7355-7359, 1994.*
Tontonoz et al. Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPARgamma and RXRalpha. Nuc Acids Res 22(25): 5628-5634, 1994.*
Zhu et al. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPARgamma) gene: Alternative promoter use and different splicing yield two mPPARgamma isoforms. Proc Natl Acad Sci USA 92: 7921-7925, 1995.*
Kliewer et al. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83: 813-819, 1995.*
Bardot et al., “PPAR-RXR Heterodimer Activates a Peroxisome Proliferator Response Element Upstream of the Bifunctional Enzyme Gene,”Biochemical and Biophysical Research Communications,192(1):37-45 (1993).
Berger et al., “Interaction of Glucocorticoid Analogues with the Human Glucocorticoid Receptor,”J. Steroid Biochem. Molec. Biol.,41(3-8):733-738 (1992).
Gearing et al., “Interaction of the peroxisome-proliferator-activated receptor and retinoic X receptor,”Proc. Natl. Acad. Sci. USA,90:1440-1444 (1993).
Giguere et al., “Identification of a receptor for the morphogen retinoic acid,”Nature,330:624-629 (1987).
Gottlicher et al., “Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor,”Proc. Natl. Acad. Sci.,89:4653-4657 (1992).
Hall et al., “Expression and Regulation ofEscherichia coli lacZGene Fusions in Mammalian Cells,”Journal of Molecular and Applied Genetics,2:101-109 (1983).
Heyman et al., “9-Cis Retinoic Acid Is a High Affinity Ligand for the Retinoid X Receptor,”Cell,68:397-406 (1992).
Hollenberg and Evans, Multiple and Cooperative Trans-Activation Domains of the Human Glucocorticoid Receptor,Cell,55:899-906 (1988).
Issemann and Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,”Nature,347:645-650 (1990).
Keegan et al., “Separation of DNA Binding from the Transcription-Activating Function of a Eukaryotic Regulatory Protein,”Science,231:699-704 (1986).
Kliewer et al., “Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors,”Nature,358:771-447 (1992).
Lazarow and Fujiki, “Biogenisis of Peroxisomes,”Ann. Rev. Cell Biol.,1:489-530 (1985).
Levin et al., “9-Cis retinoic acid stereoisomer binds and acti
Evans Ronald Mark
Forman Barry Marc
Bunner Bridget E.
Foley & Lardner LLP
Kemmerer Elizabeth
Reiter Stephen E.
The Salk Institute for Biological Studies
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