Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1991-05-22
1999-07-06
Guzo, David
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
43525411, 4353201, 435325, 435455, 435463, 536 231, 536 235, 536 241, 536 245, C12P 2100, C12N 1585, C12N 510, C07H 2104
Patent
active
059196491
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is in the field of genetic engineering, specifically directed toward the characterization and cloning of a cAMP-responsive transcription enhancer binding protein (CREB). The invention is also directed to methods for the use of the CREB protein to increase or decrease the production of specific proteins in eukaryotic cells by activating transcription of a recombinant gene in response to cAMP.
BACKGROUND OF THE INVENTION
Within the cell, transcriptional selectivity of eukaryotic genes is mediated by complex control regions composed of different combinations of promoter and enhancer elements. These regions are arrayed in tandem to allow multiple distinct regulatory factors to function coordinately to potentiate RNA synthesis. This mosaic arrangement of eukaryotic transcriptional regulatory elements provides different genes with the possibility of utilizing some of the same regulatory elements.
Enhancers are sequence-specific DNA transcriptional regulatory elements that function in cis to stimulate the transcription of genes placed in proximity to them. Generally, elements that function in cis are recognition sites for cellular proteins (Dynan, W. S. et al., Nature 316:774-778 (1985)). The cellular proteins which recognize enhancer sequences are often expressed in a manner which is tissue-specific or species-specific, or dependent upon the hormonal environment. Upon binding of the appropriate protein to the enhancer region, transcription of genes under the control of, that is, operably-linked to the enhancer is facilitated, resulting in an increased transcriptional expression of the gene, and thus in an increased expression of any protein for which the gene codes.
Enhancers are not orientation dependent elements like promoter regions are. Enhancer sequences can be oriented in either direction relative to the direction of transcription of the operably-linked gene. In addition, the sequence itself may be located anywhere in the general area of the gene, such as 5' to the promoter region, 3' to the transcriptional termination site, or even within a transcribed region of the gene, for example, in an intron. A gene may be under the transcriptional regulatory influence of multiple copies of the same enhancer, or the gene may be under the transcriptional regulatory influence of a group of different enhancers, each enhancer in the group conferring a different regulatory response on the operably-linked gene. Examples of these responses include an ability to transcriptionally respond to different agents or hormones, and tissue-specific expression of the gene.
Because of their relative orientation independence, enhancers can be located at varying distances from the promoter and transcription unit of the gene and yet still be operably-linked to that gene. The transcription unit is that sequence of a gene which is transcribed. The distance will vary with the transcriptional strength of the promoter and enhancer. Typically, on the average, enhancers are located within 200 bases upstream from the promoter site which itself determines the base at which transcription begins.
Cyclic adenosine monophosphate (cAMP) is the intracellular second messenger for many hormones or biological mediators and is known to be active in the regulation of gene expression in both prokaryotes and eukaryotes. In eukaryotes, the regulation of transcription by cAMP has been extensively studied in animals and tissue culture cells. Increasing the intracellular cAMP concentration with hormones such as glucagon or other agents such as cAMP analogs or beta-adrenergic agonists induces the transcription of many genes in a tissue-specific manner, including somatostatin (Montminy, M. R. et al., Proc. Natl. Acad. Sci. USA 83:6682 (1986)), the alpha subunit of human chorionic gonadotropin (Silver, B. J. et al., Proc. Natl. Acad. Sci. USA 84:2198 (1987); Jameson, J. L. et al., Endocrinology 119:2570 (1986); Delegeane, A. M. et al., Mol. Cell. Biol. 7:3994 (1987); Jameson, J. L. et al., Mol. and Cell. Biol. 7:3032 (1987);
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Genbank Accession No. M27691 (DNA sequence of CREB protein), release date was between Nov. 15 and Nov. 30, 1989.
Habener Joel F.
Hoeffler James P.
Guzo David
The General Hospital Corporation
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