Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-10-24
2002-07-09
Carlson, Karen Cochrane (Department: 1653)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C530S350000
Reexamination Certificate
active
06416957
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to intracellular receptors, and ligands therefor. In a particular aspect, the present invention relates to methods for selectively modulating processes mediated by farnesoid activated receptors.
BACKGROUND OF THE INVENTION
Molecular cloning studies have demonstrated that receptors for steroids, retinoids, vitamin D and thyroid hormones comprise a superfamily of regulatory proteins that are structurally and functionally related (see Evans, in
Science
240:889-895 (1988)). Known as nuclear receptors, these proteins bind to cis-acting elements in the promoters of their target genes and modulate gene expression in response to ligand therefor, such as a hormone.
Nuclear receptors can be classified based on their DNA binding properties (see Evans, supra and Glass, in
Endocr. Rev.
15:391-407 (1994)). For example, the glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors bind as homodimers to hormone response elements (HREs) organized as inverted repeats (IRs, see Glass, supra). A second class of receptors, including those activated by retinoic acid, thyroid hormone, vitamin D
3
, fatty acids/peroxisome proliferators and ecdysone, bind to HREs as heterodimers with a common partner, the retinoid X receptor (i.e., RXR, also known as the 9-cis retinoic acid receptor; see, for example, Levin et al., in
Nature
355:359-361 (1992) and Heyman et al., in
Cell
68:397-406 (1992)).
An important advance in the characterization of the nuclear receptor superfamily of regulatory proteins has been the delineation of a growing number of gene products which possess the structural features of nuclear receptors, but which lack known ligands. Accordingly, such receptors are referred to as orphan receptors. The search for activators for orphan receptors has created exciting areas of research on previously unknown signaling pathways (see, for example, Levin et al., (1992), supra and Heyman et al., (1992), supra). Indeed, the ability to identify novel regulatory systems has important implications in physiology as well as human disease and methods for the treatment thereof.
Since receptors have been identified for all known nuclear-acting hormones, a question arises as to the types of molecules that may activate orphan receptors. In view of the fact that products of intermediary metabolism act as transcriptional regulators in bacteria and yeast, such molecules may serve similar functions in higher organisms (see, for example, Tomkins, in
Science
189:760-763 (1975) and O'Malley, in
Endocrinology
125:1119-1120 (1989)). For example, a crucial biosynthetic pathway in higher eucaryotes is the mevalonate pathway (see FIG.
1
), which leads to the synthesis of cholesterol, bile acids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitamin D, steroid hormones and farnesylated proteins.
Farnesyl pyrophosphate (FPP), the metabolically active form of farnesol, represents the last precursor common to all branches of the mevalonate pathway (see FIG.
1
). As a result, FPP is required for such fundamental biological processes as membrane biosynthesis, hormonal regulation, lipid absorption, glycoprotein synthesis, electron transport and cell growth (see Goldstein and Brown, in
Nature
343:425-430 (1990)). Because of the central role of FPP in the production of numerous biologically important compounds, it is to be expected that its concentration should be closely regulated. This suggests that cells are likely to have developed strategies to sense and respond to changing levels of FPP, or its metabolites. One possible strategy by which cells can accomplish the desired regulation is to utilize a transcription factor whose activity is specifically regulated by a low molecular weight signaling molecule such as an FPP-like molecule. Potential candidates for such means to sense changing levels of FPP, or metabolites thereof, include members of the nuclear receptor superfamily, since these proteins are activated by low molecular weight signaling molecules.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have discovered that an orphan nuclear receptor, referred to as farnesoid activated receptor (i.e., FAR), is activated by farnesol and related molecules. Thus, FAR provides one of the first examples of a vertebrate transcription factor that is regulated by an intracellular metabolite. These findings suggest the existence of vertebrate signaling networks that are regulated by products of intermediary metabolism.
REFERENCES:
patent: 6184335 (2001-02-01), Evans et al.
Bradley et al., “&agr; and &bgr; thyroid hormone receptor (TR) gene expression during auditory neurogenesis: Evidence for TR isoform-specific transcriptional regulation in vivo”Proc. Natl. Acad. Sci. USA 91:439-443 (1994).
Brown and Goldstein, “Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth”J. Lipid Res. 21:505-517 (1980).
Danciger et al., “A Second Mouse Glutamic Acid Decarboxylase gene (Gad-2) Maps Proximal to Gad-1 on Chromosome 2”Mouse Genome 91:320-322 (1993).
Danielian et al., “Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors”EMBO J. 11:1025-1033 (1992).
Edmond et al., “Mevalonate Metabolism: Role of Kidneys”Science 193:154-156 (1976).
Evans, “The Steroid and Thyroid Hormone Receptor Superfamily”Science 240:889-895 (1988).
Forman and Samuels, “Interactions Among a Subfamily of Nuclear Hormone Receptors: The Regulatory Zipper Model”Mol. Endocrinol. 4:1293-1301 (1990).
Glass, “Differential Recognition of Target Genes by Nuclear Receptor Monomers, Dimers, and Heterodimers”Endocr. Rev. 15:391-407 (1994).
Goldstein and Brown, “Regulation of the mevalonate pathway”Nature 343:425-430 (1990).
Gomez et al., “Purified yeast protein farnesyltransferase is structurally and functionally similar to its mammalian counterpart”Biochem. J. 289:25-31 (1993).
Göttlicher et al., “Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor”Proc. Natl. Acad. Sci. USA 89:4653-4657 (1992).
Green and Wahli, “Peroxisome proliferator-activated receptors: finding the orphan a home”Mol. Cell Endocrinol. 100:149-153 (1994).
Hallenbeck et al., “Heterodimerization of thyroid hormone (TH) receptor with H-2RIIBP (RXR&bgr;) enhances DNA binding and TH-dependent transcriptional activation”Proc. Natl. Acad. Sci. USA 89:5572-5576 (1992).
Heyman et al., “9-Cis Retinoic Acid Is a High Affinity Ligand for the Retinoid X Receptor”Cell 68:397-406 (1992).
Issemann and Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators”Nature 347:645-650 (1990).
Kensler et al., “Effects of Retinoic Acid and Juvenile Hormone on the Induction of Ornithine Decarboxylase Activity by 12-O-Tetradecanoylphorbol-13-acetate1”Cancer Res. 38:2896-2899 (1978).
Kim et al., “cDNA Cloning of MEV, a Mutant Protein That Facilitates Cellular Uptake of Mevalonate, and Identification of the Point Mutation Responsible for Its Gain of Function”J. Biol. Chem. 267:23223-23121 (1992).
Kliewer et al., “Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3signalling”Nature 355:446-449 (1992).
Kurokawa et al., “Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding”Nature 371:528-531 (1994).
Leid et al., “Purification, Cloning, and RXR Identity on the HeLa Cell Factor with Which RAR or TR Heterodimerizes to Bind Target Sequences Efficiently”Cell 68:377-395 (1992).
Levin et al., “9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR&agr;”Nature 355:359-361 (1992).
Mangelsdorf et al., “Characterization of three RXR genes that mediate the action of 9-cis retinoic acid”Genes Dev. 6:329-344 (1992).
Marks et al., “H-2RIIBP (RXR&bgr;) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes
Evans Ronald M.
Forman Barry M.
Weinberger Cary A.
Carlson Karen Cochrane
Reiter Stephen E.
Spehar Teresa
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