Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1996-05-29
1999-07-13
Draper, Garnette D.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 71, 435 721, 435 733, 435 691, 435325, 435352, 435363, 435366, 4352523, G01N 33566
Patent
active
059225491
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for finding pharmacologically active substances by measuring the modulating effect of substances on an interleukin-5 receptor mediated signal transmission pathway in human or animal cells.
Conventional so-called "radioligand tests", in which a substance is investigated as to what extent it can displace a ligand bound to a receptor, which are used for finding pharmacologically active substances, can only be used to identify substances which affect the binding of known ligand receptor binding sites. These tests cannot tell whether the binding substance has an agonistic or antagonistic activity.
Transmembrane signal transmission systems of higher eukaryotic cells frequently consist of the following membrane-bound components: subunits; optionally is referred to as a G-protein and may be coupled both to the receptor and to its effector; secondary messenger molecules, such as cAMP, DAG, IP.sub.3, etc., e.g. an ion channel or adenylate cyclases, guanylate cyclases or phospholipases; and/or
Cell surface receptors recognise the appropriate ligands from a plurality of extracellular stimuli. The binding of the ligand to the receptor activates a signal cascade. In the case of G protein coupled receptors, the signal transmission pathway of which is relatively well understood and which mediate the activities of very different extracellular signals, this begins with the activation of the heterotrimeric G-protein.
Lower molecular weight secondary messengers such as cAMP (cyclic AMP), triggered by activation of the adenylate cyclase, cGMP (cyclic GMP), triggered by activation of the guanylate cyclase, or inositol-1,4,5-triphosphate (IP.sub.3) and diacylglycerine (DAG), triggered by activation of phospholipases, such as phospholipase C or, when hydrolases are involved, phospholipase D (Billah et al., 1989), in turn bring about intracellular changes, including the selective phosphorylation of proteins by activation of protein kinases (e.g. PKC by IP.sub.3 /DAG, PKA by cAMP), influencing the regulation of the transcription of certain genes and proliferation. (An antagonistically active substance may wholly or partially cancel the interaction caused by an agonistically active substance and the consequent change in concentration of the second messenger, or may itself lead to a reverse functional effect.) Using this signal transmission system, cells can communicate with one another and coordinate their development or the activities which they trigger.
Since a single receptor subtype (possibly in the same cell or in different cells) may be coupled to more than one effector and numerous receptor subtypes may activate the same effectors, complicated signal transmission networks are formed. The transcription factors which are activated as a result of the activation of the receptor in the signal transmission cascade (such as CREB-protein, AP1-protein) interact with regulatory DNA elements. Examples of this are CRE (CRE-element, "cAMP responsive element") or TRE (TRE="TPA responsive element"; TPA=phorbol-12-myristate-13-acetate=phorbolester), which bind CREB or AP1: many genes whose transcription is regulated by cAMP (e.g. rat somatostatin, human-a-gonadotropin, c-Fos), contain a conserved sequence, in the 5'-flanking region, as a regulatory element. The CRE-sequence is identical or similar to the palindromic octamer TGACGTCA (Montminy et al., 1990). TRE-elements contain the very similar heptameric motif TGAGTCA, which differs from the CRE-element consensus sequence only in a single nucleotide (Deutsch et al., 1988). The TRE-motif, or very similar motifs, have been identified in numerous genes the transcription of which is activated by phorbolesters (Angel et al., 1987a and b; Lee et al., 1987). Surrounding DNA sequences or protein-protein interactions with other factors determine, inter alia, the concrete regulatory phenomena at a specific gene.
Other regulatory DNA-elements are the so-called "SRE-elements" which respond to serum factors ("serum responsive element"; Treisman, 1985). SRE-elem
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Czernilofsky Armin Peter
Weyer Ulrike
Young Ian G.
Boehringer Ingelheim International GmbH
Draper Garnette D.
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