Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2000-10-19
2004-06-29
Pak, Michael (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C536S023500
Reexamination Certificate
active
06756213
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of nuclear hormone receptor proteins that are related to the retinoic acid receptor nuclear hormone receptor subfamily, recombinant DNA molecules, and protein production. The present invention specifically provides novel nuclear hormone receptor peptides and proteins and nucleic acid molecules encoding such peptide and protein molecules, all of which are useful in the development of human therapeutics and diagnostic compositions and methods.
BACKGROUND OF THE INVENTION
Nuclear Hormone Receptors
Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. The biochemical pathways through which signals are transmitted within cells comprise a circuitry of directly or functionally connected interactive proteins. One of the key biochemical mechanisms of signal transduction involves the activation of gene transcription. Many of the transcription activation pathways are controlled by the action of intracellular receptors (IRs), such as members of the nuclear hormone receptor family of proteins and their ligands. The binding of a ligand to a nuclear hormone receptor serves to translate signals generated from a variety of cellular events.
Intracellular receptors (IRs) form a class of structurally related genetic regulators scientists have named “ligand dependent transcription factors.” R. M. Evans, 240 Science, 889 (1988). Nuclear hormone receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand which has the ability to selectively bind to the IR in a way that alters gene transcription.
Ligands to the IRs can include low molecular weight native molecules, such as the hormones progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as medroxyprogesterone acetate, diethylstilbesterol and 19-nortestosterone. These ligands, when present in the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell's nucleus, where it binds to a specific gene or genes present in the cell's DNA. Once bound to DNA, the complex modulates the production of the protein encoded by that gene. In this regard, a compound which binds and IR and mimics the effect of the native ligand is referred to as an “agonist”, while a compound that inhibits the effect of the native ligand is called an “antagonist.”
Ligands to the nuclear hormone receptors are known to play an important role in health of both women and men. For example, the native female ligand, progesterone, as well as synthetic analogues, such as norgestrel (18-homonorethisterone) and norethisterone (17.alpha.-ethinyl-19-nortestosterone), are used in birth control formulations, typically in combination with the female hormone estrogen or synthetic estrogen analogues, as effective modulators of both PR and ER. On the other hand, antagonists to PR are potentially useful in treating chronic disorders, such as certain hormone dependent cancers of the breast, ovaries, and uterus, and in treating non-malignant conditions such as uterine fibroids and endometriosis, a leading cause of infertility in women. Similarly, AR antagonists, such as cyproterone acetate and flutamide have proved useful in the treatment of hyperplasia and cancer of the prostate.
Nuclear hormone hormones, one sub-family of IRs, are potent modulators of transcriptional events that together regulate the complex processes associated with differentiation homeostasis and development. The mechanism of action of these molecules is related in that the effector molecule binds to a specific intracellular receptor. This binding alters the structure of the receptor, thus increasing its affinity for specific recognition sites within the regulatory region of target genes. In this way, the nuclear hormone directs a program of events that leads to a change in cell phenotype.
Nuclear hormone hormones, thyroid hormones and certain vitamins can regulate cellular differentiation morphogenesis and homeostasis by binding to specific intracellular receptor proteins. Ligand activated receptor complexes are capable of activating or repressing transcription of a specific set of target genes. Thus, the receptor proteins are capable of reprogramming cellular function at the genomic level in response to hormonal or vitamin signals.
Retinoic Acids and Retinoic Acid Receptors
The protein provided by the present invention is a novel retinoic acid receptor isoform; the new isoform provided herein is an ortholog of the rat retinoic acid receptor alpha 2. Consequently, the new retinoic acid receptor isoform provided by the present invention may be named human retinoic acid receptor alpha 2. As used herein, the term retinoic acid (RA) is synonymous with retinoid, and the term retinoic acid receptor is synonymous with retinoid receptor.
Retinoids, or vitamin A metabolites/derivatives, have been determined to play essential roles in many aspects of development, metabolism and reproduction in vertebrates (see, for example, The Retinoids, Second Edition, Sporn et al. (Raven Press, New York, 1994)). There are two classes of retinoid receptors: the retinoic acid receptors (RARs), which bind to both all-trans retinoic acid (atRA) and 9-cis retinoic acid (9cRA), and the retinoid X receptors (RXRs), which bind only to 9cRA. These receptors modulate ligand-dependent gene expression by interacting as RXR/RAR heterodimers or RXR homodimers on specific target gene DNA sequences known as hormone response elements. In addition to their role in retinoid signalling, RXRs also serve as heterodimeric partners of nuclear receptors for vitamin D, thyroid hormone, and peroxisome proliferators (reviewed by Mangelsdorf et al., at pages 319-349 of The Retinoids, Second Edition, Spom et al. (Raven Press, New York, 1994)).
A number of studies have demonstrated that retinoids are essential for normal growth, vision, tissue homeostasis, reproduction and overall survival (for reviews and references, See Sporn et al., The Retinoids, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984)). For example, retinoids have been shown to be vital to the maintenance of skin homeostasis and barrier function in mammals (Fisher, G. J., and Voorhees, J. J., FASEB J. 10:1002-1013 (1996)). Retinoids are also apparently crucial during embryogenesis, since offspring of dams with vitamin A deficiency (VAD) exhibit a number of developmental defects (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953); Morriss-Kay, G. M., and Sokolova, N., FASEB J. 10:961-968 (1996)). With the exceptions of those on vision (Wald, G., et al., Science 162:230-239 (1968)) and spermatogenesis in mammals (van Pelt, H. M. M., and De Rooij, D. G., Endocrinology 128:697-704 (1991)), most of the effects generated by VAD in animals and their fetuses can be prevented and/or reversed by retinoic acid (RA) administration (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953); Thompson et al., Proc. Royal Soc. 159:510-535 (1964); Morriss-Kay, G. M., and Sokolova, N., FASEB J. 10:961-968 (1996)). The dramatic teratogenic effects of maternal RA administration on mammalian embryos (Shenefelt, R. E., Teratology 5, 103-108 (1972); Kessel, M., Development 115:487-501 (1992); Creech Kraft, J., In Retinoids in Normal Development and Teratogenesis, G. M. Morriss-Kay, ed., Oxford University Press, Oxford, UK, pp. 267-280 (1992)), and the marked effects of topical administration of retinoids on embryonic development of vertebrates and limb regeneration in amphibians (Mohanty-Hejmadi et al., Nature 355:352-353 (1992); Tabin, C. J., Cell 66:199-217 (1991)), have contributed to the notion that RA may have critical roles in morphogenesis an
Beasley Ellen M.
Di Francesco Valentina
Ketchum Karen A.
Wei Ming-Hui
Yan Chunhua
Applera Corporation
Celera Genomics
Karjala Justin D.
Pak Michael
LandOfFree
Nucleic acid encoding retinoic acid receptor does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Nucleic acid encoding retinoic acid receptor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nucleic acid encoding retinoic acid receptor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3299993