Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Enzyme inactivation by chemical treatment
Reexamination Certificate
1997-05-01
2002-05-14
Tate, Christopher R. (Department: 1651)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Enzyme inactivation by chemical treatment
C435S195000, C435S197000, C435S007210, C514S557000, C530S387900, C530S350000, C552S653000
Reexamination Certificate
active
06387673
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the modulation of nuclear receptor mediated processes, compounds useful therefor and methods for the identification of such compounds.
BACKGROUND OF THE INVENTION
The actions of steroids, retinoids and thyroid hormones are mediated by intracellular nuclear receptors whose coordinate activity defines the physiological response (Mangelsdorf and Evans,
Cell
83:841-850 (1995)). These receptors are all structurally related and constitute a superfamily of nuclear regulatory proteins that modulate gene expression in a ligand-dependent fashion. Previous studies have demonstrated that the 9-cis retinoic acid receptor (RXR) serves as a common heterodimeric partner for thyroid hormone receptor (TR), retinoic acid receptor (RAR), vitamin D receptor (VDR), prostanoids (PPAR), as well as numerous orphan receptors (LeBlanc and Stunnenberg
Genes
&
Dev
. 9:1811-1816 (1995)).
Transcriptional repression is an intrinsic part of endocrine physiology and contributes to feedback regulation associated with the inhibition of the physiologic response. Indeed, the thyroid hormone receptor is converted to an oncogene by mutations which block hormone binding and create a constitutive transcriptional repressor (Damm et al.
EMBO J
. 6:375-382 (1987),
Nature
339:593-597 (1989); Graf and Beug
Cell
34:7-9 (1983); Sap et al.
Nature
340:242-244 (1989)). Multiple studies on transcriptional silencing by verbA and the non-liganded thyroid hormone receptor suggest that repression is required for oncogenesis and that this process is mediated by a diffusible co-factor(s) that associates with the ligand binding domain (LBD) (Baniahmad et al.
Mol. Cell. Biol
. 15:76-86 (1995); Casanova et al.
Mol. Cell. Biol
. 14:1756-1765 (1994)).
Transcriptional co-repressors (SMRT and N-COR) have recently been identified that associate with non-liganded receptors resulting in suppression of basal transcriptional activity (see, for example, Chen and Evans
Nature
377:454-457 (1995); Chen et al.
PNAS
93:7567-7571 (1996); Horlein et al.
Nature
377:397-404 (1995); and Sande and Privalsky
Mol. Endo
. 10:813-825 (1996)).
While the mechanism of this repression is not known, chromatin remodeling has been suggested to be a component of transcriptional regulation (for review see Wolffe and Pruss.
Curr. Biol
. 6:234-237 (1996): Felsenfeld
Cell
86:13-19 (1996)). Indeed, it has been suggested that specific transcriptional activation may be involved in local changes in chromatin structure. In fact, it has recently been demonstrated that nuclear hormone receptors may utilize the CREB binding protein (CBP) or its homolog p300 (Janknecht and Hunter
Nature
383:22-23 (1996)), to function as a nuclear receptor co-factor (Chakravarti, et al.
Nature
383:99-103 (1996); Hanstein et al.
PNAS
93:11540-11545 (1996); Kamei et al.
Cell
85:403-414 (1996); Yao et al.
PNAS
93:10626-10631 (1996)). In addition to CBP/p300, multiple hormone-dependent and independent associated co-factors have been characterized (Fondell et al.
PNAS
93:8392-8333 (1996)).
Of particular interest is the recent demonstration that CPB/p300 associates with the histone acetylase P/CAF (Yang X-J et al.
Nature
382:319-324 (1996)) which displays significant sequence homology to the yeast transcription activator GCN5, also known to be a histone acetylase (Brownell et al.
Cell
84:843-851 (1996)). Further, CBP/p300 harbors intrinsic histone acetyltransferase activity, resulting in alternative or perhaps simultaneous histone acetylation (Ogryzko et al.
Cell
87:953-959 (1996)). The notion that multiple transcriptional co-activators possess acetylase activity suggests that their recruitment to a DNA template would locally destabilize nucleosomes creating a permissive state for promoter activation.
Accordingly, there is a need in the art for a further understanding of the interaction(s) between the various components involved in regulation of hormone mediated processes. A clearer understanding of these processes will facilitate the development of methods to modulate hormone mediated processes, as well as assays for the identification of compounds useful for such modulation. These and other needs in the art are addressed by the present invention.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have discovered that histone deacetylase associates with hormone receptor complexes and contributes to the repression thereof. We have further discovered that exposure of a repressed system to histone deacetylase inhibitors relieves this repression. Thus, histone deacetylase inhibitors have been found to be useful for the activation of genes responsive to hormone receptors.
In accordance with another aspect of the invention, formulations useful for modulation of hormone-mediated processes have been developed. In addition, assays have been developed for the identification of compounds useful to modulate the above-described processes.
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Chakravarti et al., “Role of CBP/P300 in nuclear receptor signalling”Nature,383:99-103 (1996).
Chen et al., “SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers” 93:7567-7571 (1996)Proc. Natl. Acad. Sci. USA.
Chen and Evans, “A Transcriptional co-repressor that interacts with nuclear hormone receptors”Nature,377:454-457 (1995).
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Evans Ronald M.
Nagy Laszlo
Foley & Lardner
Reiter Stephen E.
Tate Christopher R.
The Salk Institute for Biological Studies
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