Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1996-08-21
2002-04-30
Nguyen, Dave T. (Department: 1633)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S320100
Reexamination Certificate
active
06380373
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the novel protein termed steroid receptor coactivator-one (“SRC-1”), nucleotide sequences encoding SRC-1, as well as various products and methods useful for augmenting or downregulating the activity of one or more steroid receptors.
BACKGROUND OF THE INVENTION
The following description of the background of the invention is provided to aid in understanding the invention but is not admitted to be prior art to the invention.
Transcription is a fundamental biological process whereby an RNA molecule is formed upon a DNA template by complementary base pairing that is mediated by RNA polymerase II. Accumulated evidence indicates that numerous general transcription factors undergo a defined order of assembly at promoter-DNA elements to assure RNA polymerase II binding and initiation of transcription of target genes (for review see Zawel, L. and Reinberg, D. (1995),
Ann. Rev. Biochem
. 64, 533-561).
Activation of transcription can be achieved by direct interaction of activators with one or more components of the basal transcriptional machinery. Direct interaction between activators and the basal transcription machinery has been described for several activators (Stringer, K. F. et al., (1990),
Nature
345, 783-785; Kashanchi, F. et al., (1994),
Nature
367, 295-299; Sauer, F. et al., (1995),
Nature
375, 162-164).
Optimal transactivation by an activator is likely to require additional factors termed adaptors or coactivators. These factors seem to play a key regulatory role in bridging or stabilizing the activator with general transcription factors in the core transcriptional machinery. The ability of an activator to squelch or inhibit transactivation of a target gene by another transactivator suggests that they compete for a limited amount of cofactor(s) required for the transactivation process and furthers the concept that coactivators are required for efficient transactivational function (Flanagan, P. M. et al., (1991),
Nature
350, 436-438).
It has been postulated that steroid receptors regulate transcription via interactions with the basal transcriptional machinery. However, the finding that squelching occurs between members of the steroid receptor superfamily, indicates that an additional factor(s) or coactivator(s) is important for efficient ligand-inducible target gene expression by members of this superfamily (Meyer, M. E. et al., (1989),
Cell
57, 433-442; Conneely, O. M. et al., (1989), “Promoter specific activating domains of the chicken progesterone receptor.” In Gene Regulation by Steroid Hormones IV. A. K. Roy and J. Clark, eds. (New York, Berlin, Heidelberg, London, Paris, Tokyo: Springer-Verlag), pp. 220-223; Bocquel, M. T. et al., (1989),
Nucleic Acids Res
. 17, 2581-2594; Shemshedini, L. et al., (1992),
J. Biol. Chem
. 261, 1834-1839). No such functional coactivator for this superfamily has previously been identified.
Steroid receptors belong to a superfamily of ligand inducible transcription factors which regulate hormone responsive genes and thereby affect several biological processes including cell growth and differentiation. The steroid/thyroid hormone receptor superfamily can be divided into two types (termed A and B) based on their characteristic association with heat shock proteins, binding to DNA and their ligand-dependent transactivation function (Tsai, M. -J. and O'Malley, B. W. (1994),
Ann. Rev. Biochem
. 63, 451-486).
One steroid receptor, the human progesterone receptor (hPR), is expressed in cells as two isoforms: PR
B
of 120 kDa and PR
A
of 94 kDa. The A isoform is a shorter transcript of PR, lacking the most N-terminal 164 amino acids of the B receptor (Kastner, P. et al., (1990),
EMBO J
. 9, 1603-1614; Wei, L. L et al., (1987),
Biochem
. 26, 6262-6272). Although they display similar ligand specificities and DNA-binding affinities in vitro, the transcriptional activity of the two receptor isoforms show different promoter and cell specificities when assayed in intact cells (Chalepakis, G. et al., (1988),
Cell
53, 371-382; Tora, L. et al., (1988),
Nature
333, 185-188; Tung, L. et al., (1993),
Mol. Endocrinol
. 7, 1256-1265).
Like other members of the steroid receptor superfamily, the hPRs are modular proteins containing a ligand binding domain (LBD) at the C-terminus and a centrally located DNA binding domain (DBD). Two regions in hPR have been thought to contain transcriptional activation functions (AFs). One is located at the N-terminus (AF1) and the other (AF2) is located within the LBD (Tora, L. et al., (1989),
Cell
59, 477-487; Gronemeyer, H. (1991),
Ann. Rev. Genet
. 25, 89-123). Recent results indicate that the hPR
B
specific 164 amino acid fragment may contain an additional activation function (Sartorius, C. A. et al., (1994),
Mol. Endocrinol
. 8, 1347-1360) that is required for maximal transactivation of the full-length receptor.
Activation of a steroid receptor is a complex multi-step process that involves structural and functional alterations of receptor which promote specific binding to DNA hormone-responsive elements (HREs) to modulate the target gene expression (for review see Tsai, M. -J. and O'Malley, B. W. (1994),
Ann. Rev. Biochem
. 63, 451-486). Thus, steroid receptors must undergo a rather complex multi-step activation process to achieve their ultimate transactivational function.
Coactivators have been implicated widely in nuclear steroid receptor function. Transcriptional interference experiments between members of the steroid receptor superfamily suggested that coactivators are limiting and interact, either directly or indirectly, with the receptor protein in vivo to modulate transcription. However, as noted above, no such functional coactivator for this superfamily has previously been identified.
SUMMARY OF THE INVENTION
The present invention relates to SRC-1 polypeptides, nucleic acids encoding such polypeptides, cells containing such nucleic acids, antibodies to such gene products, assays utilizing such polypeptides, and methods relating to all of the foregoing. In particular, this invention relates to methods for augmenting or downregulating the activity of one or more steroid receptors.
The present invention is based upon the isolation and characterization of a new protein which we have designated steroid receptor coactivator-1, or SRC-1. We have determined that modulation of SRC-1 activity is useful in therapeutic procedures and thus the present invention provides several agents and methods useful for modulating steroid hormone responses and activities, including modulation of the activity of other transactivators.
The isolated, purified, and/or enriched SRC-1 polypeptides and/or nucleic acids can be used to transactivate a steroid receptor and thereby promote the level of transcription in an organisms or cell. Administration of the appropriate material can be accomplished by one skilled in the art using methods described herein. For example, one or more transfected and/or transformed cells can be used to perform a gene therapy based treatment where activity of steroid receptors may be involved. Examples of disorders or conditions that involve the activity of steroid receptors include malignancies of the reproductive endocrine system and inflamation and immunity disorders, such as those described in U.S. patent application Ser. No. 08/479,913, filed Jun. 7, 1995, incorporated herein by reference in its entirety, including any drawings. Examples of other disorders or conditions are listed in references available to those skilled in the art such as the Physicians' Desk Reference and include endocrine disorders, rheumatic disorders, collagen disorders, dermatologic diseases, allergic states, ophthalmic diseases, gastrointestinal diseases, respitory diseases, hematologic disorders, breast cancer, endometriosis, hyperproliferative disorders including cancer and others. Alternatively, methods of the invention may be used to inhibit transcription. For example, a truncated form of SRC-1 can be used as a dominant negative inhibitor of receptor
O'Malley Bert
Onate Sergio
Tsai Ming-Jer
Tsai Sophia Y.
Baylor College of Medicine
Lyon & Lyon LLP
Nguyen Dave T.
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