Multimeric forms of members of the steroid/thyroid superfamily of receptors with the ultraspiracle receptor

• US 6,281,330 B1
• Filed: 06/05/1995
• Issued: 08/28/2001
• Est. Priority Date: 03/22/1990
• Status: Expired due to Term

• Current Assignee: The SALK Institute For Biological Studies
• Original Assignee: The SALK Institute For Biological Studies
• Inventors: Evans, Ronald M., Yao, Tso-Pang, Segraves, William A., Oro, Anthony E., Mc Keown, Michael B.
• Primary Examiner(s): Sisson, Bradley L.
• Application Number:
  US08/486,403
• Time in Patent Office: 2,276 Days
• Field of Search: 530/350, 530/380, 530/858, 530/399, 930/120, 930/130, 930/180
• US Class Current: 530/324
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C07K 14/44 from protozoa
• CPC Class Codes: C07K 14/70567 Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
• CPC Class Codes: C07K 14/721 Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
• CPC Class Codes: C12N 15/85 for animal cells
• CPC Class Codes: C12N 2830/00 Vector systems having a special element relevant for transcription
• CPC Class Codes: C12N 2830/002 inducible enhancer/promoter combination, e.g. hypoxia, iron, transcription factor
• CPC Class Codes: C12N 2830/75 from invertebrates
• CPC Class Codes: C12Q 1/6897 involving reporter genes operably linked to promoters

Abstract

In accordance with the present invention, it has been discovered that various members of the steroid/thyroid superfamily of receptors can interact with the insect-derived ultraspiracle receptor, to form multimeric species. Accordingly, the interaction of at least one member of the steroid/thyroid superfamily of receptors with at least the dimerization domain of the ultraspiracle receptor modulates the ability of said member of the steroid/thyroid superfamily of receptors to transactivate transcription of genes maintained under hormone expression control in the presence of the cognate ligand for said member of the superfamily.

Claims

1. An isolated multimeric receptor, wherein at least one subunit of said multimeric receptor is an ultraspiracle receptor, and wherein at least one subunit of said multimeric receptor is a hormone binding protein, wherein said hormone binding protein is characterized by having a DNA-binding domain having the amino acid sequence set forth in SEQ ID NO:

3.

2. A multimeric receptor according to claim 1 wherein said multimeric receptor is a heterodimer.

3. A multimeric receptor according to claim 1 wherein said multimeric receptor is a heterotrimer.

4. A multimeric receptor according to claim 1 wherein said multimeric receptor is a heterotetramer.

5. A multimeric receptor according to claim 1 wherein said hormone binding protein is an insect derived member of the steroid/thyroid superfamily of receptors.

6. A multimeric receptor according to claim 1 wherein said hormone binding protein is the ecdysone receptor.

7. A multimeric receptor according to claim 1 wherein said hormone binding protein is PPAR, VDR, TRα

, TRβ

, RARα

, RARβ

or RARγ

.

8. An isolated multimeric receptor comprising a first subunit and a second subunit, wherein said first subunit is an ultraspiracle receptor and wherein said second subunit is a non-insect member of the steroid/thyroid hormone superfamily of receptors.

9. An isolated receptor according to claim 8 wherein said second subunit is peroxisome proliterator-activated receptor (PPAR).

10. An isolated receptor according to claim 8 wherein said second subunit is vitamin D receptor (VDR).

11. An isolated receptor according to claim 8 wherein said second subunit is thyroid hormone receptor (TR).

12. An isolated receptor according to claim 8 wherein said second subunit is retinoic acid receptor (RAR).

13. An isolated receptor according to claim 11 wherein said thyroid hormone receptor is thyroid hormone receptor alpha (TRα

).

14. An isolated receptor according to claim 11 wherein said thyroid hormone receptor is thyroid hormone receptor beta (TRβ

).

15. An isolated receptor according to claim 12 wherein said retinoic acid receptor is retinoic acid receptor alpha (RARα

).

16. An isolated receptor according to claim 12 wherein said retinoic acid receptor is retinoic acid receptor beta (RARβ

).

17. An isolated receptor according to claim 12 wherein said retinoic acid receptor is retinoic acid receptor gamma (RARγ

).