Antisense modulation of SRC-1 expression

Details Antisense modulation of SRC-1 expression Antisense modulation of SRC-1 expression

2000-11-27

2001-09-25

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

Method of regulating cell metabolism or physiology

C514S04400A, C536S023100, C536S024100, C536S024310, C536S024500, C435S006120, C435S091100, C435S325000, C435S366000, C435S440000, C435S455000

Reexamination Certificate

active

06294382

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of SRC-1. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human SRC-1. Such oligonucleotides have been shown to modulate the expression of SRC-1.
BACKGROUND OF THE INVENTION
Steroid, thyroid and retinoid hormones produce a diverse array of physiologic effects through the regulation of gene expression. Upon entering the cell, these hormones bind to a unique group of intracellular nuclear receptors which have been characterized as ligand-dependent transcription factors. This complex then moves into the nucleus where the receptor and its cognate ligand interact with the transcription preinitiation complex affecting its stability and ultimately the rate of transcription of the target genes.
The interactions of the liganded receptor with the specific elements in the promoter region are mediated by two classes of molecules; corepressors, which inhibit transactivation and coactivators, which enhance transactivation.
SRC-1 (also known as steroid receptor coactivator-1, F-SRC-1 and NcoA-1) is a member of the growing family of transcriptional coactivators. SRC-1 was first isolated as a protein that interacted with and enhanced human progesterone receptor (hPR) transcriptional activity in a hormone-dependent manner without altering the basal activity of the promoter (Onate et al.,
Science,
1995, 270, 1354-1357). Subsequently, SRC-1 has been shown to enhance the transcriptional ability of other steroid receptors including the estrogen receptor (Kalkhoven et al.,
Embo J.,
1998, 17, 232-243), glucocorticoid receptor (Onate et al.,
Science,
1995, 270, 1354-1357), thyroid hormone receptor (Jeyakumar et al.,
Mol. Endocrinol.,
1997, 11, 755-767), retinoic acid receptor (Yao et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1996, 93, 10626-10631) and retinoid X receptor (Westin et al.,
Nature,
1998, 395, 199-202), all in a ligand-dependent manner.
SRC-1 contains an intrinsic histone acetyltransferase activity specific for histones H3 and H4. It was proposed that this intrinsic activity allows the protein to disrupt the compacted chromatin structure and enhance the formation of a stable preinitiation complex (Spencer et al.,
Nature,
1997, 389, 194-198).
SRC-1 has also been shown to mediate transactivation through interactions with c-Jun, c-Fos and NF-kappa-B subunits (Lee et al.,
J. Biol. Chem.,
1998, 273, 16651-16654; Na et al.,
J. Biol. Chem.,
1998, 273, 10831-10834).
Tissue distribution studies showed that SRC-1 message is expressed at high levels in the heart, placenta, skeletal muscle, and pancreas but at very low levels in the lung, liver and kidney (Li and Chen,
J. Biol. Chem.,
1998, 273, 5948-5954). In the rat, a gender-related difference in expression was found in the anterior pituitary, with females expressing 40% less SRC-1 than males (Misiti et al.,
Endocrinology,
1998, 139, 2493-2500).
Variations in SRC-1 levels have recently been used as a predictive marker of tamoxifen response in recurrent breast cancer. These studies showed that SRC-1 levels were lower in tumors from patients that did not respond to tamoxifen treatment, suggesting that high levels of SRC-1 indicated a favorable response to tamoxifen (Berns et al.,
Breast Cancer Res. Treat.,
1998, 48, 87-92).
To date, strategies aimed at inhibiting SRC-1 function have involved the use of mutant forms of the protein and gene knock-outs in mice.
By localizing functional domains within the protein, it was demonstrated that a truncated version of the protein lacking the C-terminal domain could act as a dominant-negative repressor of transcription (Onate et al.,
Science,
1995, 270, 1354-1357). These results lend further support to the role of SRC-1 as a coactivator.
In studies of mice lacking the SRC-1 gene, both hetero-and homozygous SRC-1 null mice appeared to be normal with no obvious external differences from the wild-type. However, internal organs such as the uterus, prostate, testis and mammary glands showed decreased growth and development in response to steroid hormones. These results indicated that SRC-1 is required for efficient hormone action in vivo (Xu et al.,
Science,
1998, 279, 1922-1925).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of SRC-1. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting SRC-1 function. Antisense oligonucleotides, therefore, may provide a promising new pharmaceutical tool for the effective and specific modulation of SRC-1 expression.
SUMMARY OF THE INVENTION
The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding SRC-1, and which modulate the expression of SRC-1. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of SRC-1 in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of SRC-1 by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention employs oligomeric antisense compounds, particularly oligonucleotides, for use in modulating the function of nucleic acid molecules encoding SRC-1, ultimately modulating the amount of SRC-1 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding SRC-1. As used herein, the terms “target nucleic acid” and “nucleic acid encoding SRC-1” encompass DNA encoding SRC-1, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as “antisense”. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of SRC-1. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.
It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding SRC-1. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic

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