Process for inhibiting the transcription of genes

Details Process for inhibiting the transcription of genes Process for inhibiting the transcription of genes

1996-01-22

2000-07-18

Elliott, George C.

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

435 691, 4353201, 435325, 514 2, 536 241, C12Q 168, C12N 1563, A61K 3700, C07H 2104

Patent

active

060905425

DESCRIPTION:

BRIEF SUMMARY
The invention relates to influencing the transcription of genes.
Inducible gene expression depends, amongst other things, on the inducible activation of proteins, regulating transcription by interacting with cis-regulatory DNA elements. The activity of these proteins, referred to as transcription factors, can be regulated by their de novo-synthesis; this strategy requires additional factors affecting the gene for the transcription factor. On the other hand, posttranslational mechanisms for the activation of transcription factors have the advantage of being quicker than mechanisms at the transcription level. For control of the activity of transcription factors, inhibitory protein subunits play, inter alia, an important role. An example for this is IP-1, a Leucine zipper protein, inhibiting AP-1. In this case the inhibitory subunit assumes the function of a trans-dominant negative regulator based on a structural homology with the activator. The NF-KB system is a system in which the inhibitory subunits show no homology with the DNA-binding subunits. The inhibitory subunits of NF-KB and the related factors are referred to as IkB proteins, reversibly inhibiting the binding of the transcription factor to DNA (Baeuerle and Baltimore, 1988a,b).
NF-KB, a heterodimeric factor consisting of a 50 kDa (p50) and a 65 kDa (p65) DNA-binding subunit, contributes to the so-called "immediate-early" activation of defence genes if cells are exposed to primary or secondary pathogenic stimuli (Baeuerle, 1991, Baeuerle and Baltimore, 1991).
The transcription factor NF-KB (Grimm and Baeuerle, 1993; Blank et al., 1992; Nolan and Baltimore, 1992) is, inter alia, activated by treating cells with bacteriological stimuli (inter alia LPS), viruses (inter alia HIV virus type 1), viral products, parasites, inflammatory cytokines (inter alia TNF-.alpha., TNF-.beta., IL-1, IL-2), T-cell mitogens (inter alia lectines), protein synthesis inhibitors (inter alia cycloheximide), physical stress (UV-light, gamma radiation), oxidative stress (inter alia hydrogen super oxide) and tumour promoters (inter alia phorbol ester) (Baeuerle, 1991).
The activation of NF-KB in response to a large number of pathogenic stimuli is carried out by a mechanism which, as yet, has not been completely explained. Subsequent to activation, NF-KB is transferred into the cell nucleus and the target genes are activated by active NF-KB. It is assumed that reactive oxygen compounds play a role as messengers during the activation of NF-KB (Schreck et al., 1991).
It has been proven that the activation of NF-KB is connected with the release of the inhibitory subunit IkB from a cytoplasmic complex including the DNA-binding subunits p50 and Rel-A (formerly referred to as p65) (Baeuerle and Baltimore 1988 a,b). As a result of experiments with cell extracts it was assumed that the release of the inhibitory subunit IkB-.alpha. and the activation of NF-KB was due to the phosphorylation of IkB-.alpha. by protein kinase C (PKC) and other kinases (Shirakawa and Mizel, 1989; Ghosh and Baltimore, 1990; Kerr et al., 1991).
The following gene classes are controlled by NF-KB; they all contain a decameric DNA motif with the consensus sequence 5'-GGGRNNTYCC-3'(SEQ. ID. NO. 1) which is recognised by NF-KB: viral genes (HIV-1-, cytomegalo-, SV 40-, adenovirus), immune receptors (inter alia light immunoglobulin-k-chains, T-cell receptor B, adhesion molecule 1), cytokine (IFN-.beta., GM-CSF, IL-2, IL-6, TNF-.alpha., TNF-.beta.), acute phase proteins (inter alia angiotensinogen), transcription factors (inter alia "interferon regulatory factor-1", NF-KB precursor p50), vimentine. (Baeuerle, 1991).
In view of numerous pathological conditions in which the activation of the genes by the transcription factor NF-KB takes part, there is a need for NF-KB inhibitors to inhibit the transcription of genes which could have a harmful effect on the organism.
Prior art solutions suggested for inhibiting the expression of genes under the transcriptional control of NF-KB, are based on a control of the dissociation

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