 Controlled release osmotic infusion system |
| Obiects of the invention It is an object of the invention to provide a portable controlled release ... |
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| Syringe-filling medication dispenser |
| The present invention is directed to a medication dispenser which can be used with one or more ... |
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| Implantable cardiac electrode with rate controlled drug delivery |
| The present invention provides a means for controllably releasing one or more drugs from an ... |
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| Method for enhancing the anti-tumor therapeutic index of interleukin-2 |
| The present invention is a method for enhancing the therapeutic index of IL-2 treatment. The method ... |
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| Ribozyme amplified diagnostics |
| A system is described for the use of a ribozyme as a diagnostic tool for detecting the presence of ... |
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| Hairpin ribozymes |
| We claim: 1. A Hairpin ribozyme lacking a substrate moiety, comprising between six and eight bases ... |
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| Modified ribozymes |
| We claim: 1. An RNA molecule with catalytic activity comprising at least one modified nucleoside, ... |
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| Regulatable RNA molecule |
| Construction of a regulatable ribozyme is described in which a ribozyme sequence is linked to a ... |
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| Apparatus for diverse chemical synthesis using two-dimensional array |
| OF THE INVENTION While the present invention will be described with reference to certain specific ... |
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Transcriptional activators with graded transactivation potential
| Details |
Inventors: Baron, Udo; Gossen, Manfred; Bujard, Hermann;
Assignee: BASF Aktiengesellschaft (Ludwigshafen, DE); Baron; Udo (St. Ilgen, DE)
Primary Examiner: McKelvey; Terry
Assistant Examiner:
Attorney, Agent or Firm: Lahive & Cockfield, LLP, DeConti, Jr.; Giulio A., Kara; Catherine J.
Transcriptional activators which differ in their activation potential by more than 3 orders of magnitude are provided. The transactivators are fusions between a DNA binding protein (e.g., a Tet repressor) and minimal transcriptional activation domains derived from Herpes simplex virus protein 16 (VP16). Substitution mutations at amino acid position 442 within the minimal VP16 domain provide transactivators with differing transactivation ability. Moreover, chimeric activation domains comprising both wild type and mutant minimal VP16 domains provide additional variants with differing transactivation ability. Various aspects of the invention pertain to nucleic acid molecules, vectors, host cells, fusion proteins, transgenic and homologous recombinant organisms and methods of regulating gene transcription. |
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DETAILED DESCRIPTION OF THE INVENTION In the following subsections, transactivator fusion proteins of the invention having graded transcriptional activation potentials are primarily described in the context of tetracycline-controlled transcription activation systems, as a representative example of a system using VP16-derived activation domains.
However, as will be appreciated by the skilled artisan, the novel VP16-derived activation domains of the invention can be used in combination with other DNA binding domains, by applying the same approaches described herein for the tet system.
Non-limiting examples of other DNA binding domains/proteins that have well characterized DNA binding specificities and that previously have been used in chimeric transactivator fusion proteins include GAL4 (see e.
g.
, Sadowski, I.
et al.
(1988) Nature 335:563-564), LexA (see e.
g.
, Brent R.
and Ptashne M.
(1985) Cell 43, 729-36), LacR (see e.
g.
, Labow et al.
(1990) Mol.
Cell.
Biol.
10:3343-3356; Baim et al.
(1991) Proc.
Natl.
Acad.
Sci.
USA 88:5072-5076) and steroid hormone receptors (Ellliston, J.
F.
et al.
(1990) J.
Biol.
Chem.
265, 11517-11521).
Moreover, the components and methods of the current invention can be applied to the regulatory system described in Wang Y.
, et al.
(1994) Proc.
Natl.
Acad.
Sci.
USA 9, 8180-8184, which utilizes a fusion of GAL4, a hormone receptor and VP16.
The tetracycline controlled transcription activation system has been described previously (Gossen, M.
, and Bujard, H.
(1992) Proc.
Natl.
Acad.
Sci.
U.
S.
A 89, 5547-5551) and functions as an efficient genetic switch in a variety of eukaryotic cells including mammalian (Resnitzky, D.
, et al.
(1994) Mol.
Cell.
Biol 14, 1669-1679), plant (Weinmann, P.
, et al.
(1994) Plant J 5, 559-569) and yeast cells.
It also allows to effectively control gene activities at the level of organisms as shown in plants (Weinmann, P.
, et al.
(1994) Plant J 5, 559-569), mice (Kistner, A.
, et al.
(1996) Proc.
Natl.
Acad.
Sci.
U.
S.
A.
93, 10933-10938) and Drosophila
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Gene Therapy 
