Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-07-06
2001-06-19
Jones, W. Gary (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C435S091210, C435S091510, C514S04400A
Reexamination Certificate
active
06248520
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to isolated nucleic acid molecules which encode nuclear hormone receptor coactivators, conserved variants thereof, fragments thereof, or analogs or derivatives thereof, which have applications in modulating the expression of genes in the nucleus.
BACKGROUND OF THE INVENTION
Nuclear hormone receptors are intracellular receptors that play important roles in expression of genes involved in physiological processes that include cell growth and differentiation, development, and homeostasis. Broadly, these receptors are members of a superfamily of receptors, whose members recognize similar DNA sequences that contain two or more hexanucleotide DNA-binding half-sites arranged as direct repeats or inverted repeats. It is through this recognition that these receptors are able to regulate the expression of genes in the nucleus, and thereby regulate cell differentiation, development and homeostasis. The thyroid hormone receptor (TR&agr;) is an example of such a receptor. Upon activation, this receptor is involved in the expression of specific genes encoding energy-related enzymes, increasing their synthesis and consequently increasing the basal metabolic rate of the animal. [Lehninger et al.
Principles of Biochemistry,
2
d Edition.
Worth Publishers, New York, 1993, p. 752]. The thyroid hormone receptor also plays an important role in development and maintenance of various brain and muscle tissues including but not restricted to neuronal development in neonate, neuronal cell migration, axonal growth and myelination in brain, and keeping body temperatures in muscles. Moreover, TR&agr; is identical with protooncogene c-ErbA. The viral oncoprotein v-ErbA as well as some mutant TR&agr; causes hepaocellular carcinoma.
Another example of a nuclear hormone receptor is the estrogen receptor. Upon binding with its corresponding hormone, estradiol, and its activation, this receptor plays a crucial role in regulating the development of the secondary sexual characteristics of females, and the controlled differentiation of cells involved in such development.
Still another example of a nuclear hormone receptor is the androgen receptor, which upon binding with testosterone, its corresponding hormone, and activation, is intimately involved in the development of secondary sexual characteristics of males, and cellular differentiation needed to produce such secondary characteristics. Still another nuclear hormone receptor comprises the peroxisome proliferator activated receptors (PPARs), and isoforms thereof. Upon binding with a peroxisome proliferator such as clofibric acid, nafenopin, or Wy-14,683, as well as by some fatty acids, and activation, this receptor induces expression of a number of genes, including those that encode coenzyme A oxidase and CYP45 0 A6. Furthermore, PPAR&ggr;2, an isoform of PPAR, is involved in the regulation of the differentiation fat cells. Also included in this superfamily of nuclear hormone receptors are the trans-retinoic acid receptor (RAR), the 9-cis retinoic acid receptor (RXR), the vitamin D receptor (VDR), and the progesterone receptor, which plays a critical role in forming and shedding of the endometrium during the menstrual cycle of a mature female.
These nuclear hormone receptors, upon activation, are able to regulation expression of genes because they directly bind to specific DNA sequences called hormone response elements, which are located either downstream or up stream from a gene whose transcription is regulated by the receptor. Upon the ligand dependent binding of the hormone to the receptor, the receptor changes its conformation in a manner that activates or suppresses the transcription of the gene to which it binds, and ultimately regulates biological processes such as cell growth, differentiation, and homeostasis.
In order for these receptors to regulate gene expression, they must be activated by ligands and bound to DNA. It has been determined that hormones that are generally small and hydrophobic, and are able diffuse across a plasma membrane and cytoplasm of a cell, bind to these receptors, and are involved in their activation. Examples of such hormones include, steroid hormones, such as testosterone, &bgr;-estradiol, aldosterone, cortisol and progesterone, thyroid hormones such as thyroxine (T
4
) and triiodothyroxine (T
3
) and vitamin D (in vertebrates) along with hormones derived therefrom. These hormones, also generally referred to as ligands, bind to nuclear hormone receptors, which is crucial to the activation of these of these receptors, their regulation of gene expression and ultimately their mediation of cell differentiation and development of an organism. The thyroid receptor also plays an important role in development and maintenance of various brain and muscle tissues.
However, in order for a specific hormone to bind to a specific nuclear hormone receptor such that the transcription of a particular gene is regulated, additional proteins forming a complex must also bind to the receptor. These proteins, referred to herein as coactivators, are required for functional interactions between the receptor and the gene whose transcription is regulated. One type of coactivator, a complex of thyroid hormone receptor-associated proteins (TRAPS) operates in conjunction with thyroid hormone to activate thyroid receptors. Together, the thyroid hormone receptor and the associated coactivator activate transcription by the general transcription machinery of the genes in the nucleus to which thyroid receptor binds. This activation involves interactions of the thyroid hormone receptor-coactivator complex with components of the general transcriptional machinery, itself comprised of RNA polymerase II, associated general initiation factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH), and general activators in the upstream stimulatory activity (USA). The coactivator function of the TRAPS was demonstrated in a cell free system reconstituted with purified DNA templates and components of the general transcription machinery, indicated that they act more directly to facilitate preinitiation complex formation on function [Fondell, J. D., Ge, H. & Roeder, R. G. (1996)
Proc. Natl. Acad. Sci. USA
93, 8329-8333, which is hereby incorporated by reference herein in its entirety].
Hence, what is needed is isolation of TRAPS, including nucleic acid molecules which encode TRAPS, and the amino acid sequences of such TRAPS, so that numerous pharmaceuticals can be developed and assayed for their ability to regulate transcription of genes in vivo.
What is also needed are pharmaceutical compositions that can modulate the activation of nuclear hormone receptors, and thereby modulate expression of genes in an organism. Since nuclear hormone receptors play a vital role in mediating gene expression, cell growth and differentiation, development of an organism, and homeostasis, such modulation provides a valuable tool for treating numerous cancers, which involve uncontrolled differentiation, particularly in tissues comprising the sexual and reproductive organs, and in brain, muscle or adipocyte tissue.
What is also need are pharmaceutical compositions that can increase expression of genes that for some inexplicit able reason, are not sufficiently expression in vivo, resulting in a handicap deformity, or illness to the organism.
SUMMARY OF THE INVENTION
The present invention relates to isolated nucleic acid molecules which encode Thyroid Receptor-Associated Proteins (TRAPS), which are coactivators that are included in protein complexes, and bind to nuclear hormone receptors in a ligand (hormone)-dependent manner so that the receptor regulates the transcription of a particular gene. Examples of nuclear hormone receptors to which TRAPS of the invention bind include, but are not limited to, &agr; and &bgr; isoforms of thyroid hormone receptor (TR), having thyroid hormone as corresponding particular hormone, vitamin D receptor (VDR) having vitamin D as a corresponding hormone, isoforms &agr;, &bgr;, and &ggr; of retin
Fondell Joseph D.
Ito Mitsuhiro
Roeder Robert G.
Xingyuan Chao
Jones W. Gary
Klauber & Jackson
Taylor Janell E.
The Rockefeller University
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