Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1997-05-08
1999-09-28
Allen, Marianne P.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
536 235, 530350, G01N 3353, C12N 1512, C07K 14705
Patent
active
059587105
DESCRIPTION:
BRIEF SUMMARY
This invention relates to cellular nuclear receptors and their uses.
A large family of nuclear receptors which confer cells with responsiveness to molecules such as retinoid acid, vitamin D, steroid hormones and thyroid hormones has been identified. Extensive studies have shown that the members of this superfamily of nuclear receptors activate and/or repress gene transcription through direct binding to discrete cis-acting elements termed "hormone response elements" (HRE). It has been shown that these HRE's comprise repeats of consensus palindromic hexanucleotide DNA motifs. The specificity of the HRE's is determined by the orientation of, and spacing between, halfsites (i.e. half a palindromic sequence)(Umenesono K., et al, 1991 Cell 65, 1255-1266).
Specific DNA binding is mediated by a strongly-conserved DNA binding domain, containing two zinc fingers, which is conserved among all thus discovered nuclear receptors. Three amino acids at the C-terminal base of the first zinc finger (known as the "P-box") are important for the recognition of the half site nucleotide sequence. Members of the nuclear receptor superfamily have been classified into different groups on the basis of the amino acid sequence within the P box.
All members of the nuclear receptor superfamily also contain a hypervariable N-terminal domain and a ligand-binding domain containing some "patches" of conserved sequence. One of these is called the "Ti-domain".
Molecules which are thought to be nuclear receptors, as they are structurally related to cliaracterised receptors, but for which no ligand has been found, are termed "orphan receptors". Many such orphan receptors have been identified (see for example Evans R. M. (1988) science 240,889-895 and O'Malley, B. (1990) Mol. Endocrinol. 4 363-369)
We have now unexpectedly identified, initially in rat a new orphan receptor, which is related to the known estrogen receptor ER.alpha., and which we have designated "ER.beta." (specifically "rER.beta." in rat). In this specification "ER.beta." will be used to refer to the receptors hER.beta. or rER.beta. or related receptors. The nucleotide and amino acid sequences of rER.beta. have now been determined and are shown in FIG. 1. We have also identified a human ER.beta.--"hER.beta.", the amino acid DNA and sequences of which are shown in FIG. 13A and 13B respectively.
According to one aspect of the invention there is provided a novel estrogen receptor-related nuclear receptor, hereinafter termed "ER.beta." having the amino acid sequence of FIGS. 1, FIG. 13A or 14A or substantially the same amino acid sequence as the amino acid sequence shown in FIGS. 1, 13A or 14A or an amino acid sequence functionally similar to those sequences. The isolated receptor may be particularly useful in the search for molecules for use in treatment of diseases or conditions such as cardiovascular diseases, central nervous system diseases or conditions or osteoporosis, prostate cancer or benign prostatic hyperplasia.
The receptor of the invention may also be used in the testing of environmental chemicals for estrogenic activity. There has been increasing concern over the effect of various chemicals released into the environment on the reproduction of humans and animals. Threats to the reproductive capabilities of birds, fish, reptiles, and some mammals have become evident and similar effects in humans have been proposed. Substantial evidence is now emerging which shows that exposure to certain chemicals during critical periods of foetal life may distort the development of the reproductive organs and the immune and nervous systems. On the basis of possible parallels between actual wildlife effects, seen for example in birds and seals living in highly polluted areas, and proposed effects in humans, in combination with documented human reproductive effects caused by prenatal exposure to the pharmaceutical estrogen, diethyl stilbestrol (DES), "estrogenic" chemicals have been proposed to threaten the reproductive capability of both animals and humans. Among the chemicals known or su
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Enmark Eva L. K.
Gustafsson Jan-Ake
Kuiper Georg
Allen Marianne P.
Garabedian Todd E.
Karo Bio AB
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