Inhibitors of transcription

A number of antibiotics function by inhibiting transcription. Actinomycin D (see Chap. 16) is an example of one that exerts its effect by binding to the DNA template it can also block DNA replication. 

Question Would actinomycin D be expected to inhibit transcription in both bacteria and eukaryotes  

because in binding to the template, it recognizes a structural feature of the DNA double helix and therefore cannot discriminate between the two types of organism. 

Question Arc there inhibitors that discriminate between transcription in bacteria and eukaryotes  

Examples are rifampicin and streptolydigin, which bind only to bacterial RNA polymerase and block its action a-amanitin binds only to eukaryotic RNA polymerase II and, to a lesser extent, to RNA polymerase III to block their actions. 

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Disubstituted4-dimethylaminopyridines as artificial inhibitors of transcription factors involved in HIV replication 97YGK697. 

The Rb locus that is affected by the mutation, and that causes retinoblastoma, is a tumour suppressor gene. It encodes the Rb protein which is an inhibitor of transcription. The Rb protein controls the expression of three genes, which are essential for cell proliferation by forming a complex with, and thus inactivating, a transcription factor for these genes. These are ... 

Several tetrahedral cuprous phenanthroline complexes, known inhibitors of transcription, were tested against integrase and shown to be reasonably effective inhibitors [56] IC50 values in the range of 1-10 jiMwere determined (for example, the neocuproine-Cu+ complex, XII). Analyses of the mode of inhibition demonstrated that these compounds act noncompetitively, and that inhibition does not correlate with inhibition of DNA binding. Thus, it has been proposed that these metal chelates may act at a site distant from the active site, or perhaps in the context of an enzyme-DNA complex. 

The precise functions of the subunits of the core enzyme are not known. /3 is a basic (positively charged) polypeptide thought to be involved in DNA binding. The j8 subunit is the site of binding of several inhibitors of transcription and is thought to contain most or all of the active sites for phosphodiester bond formation. The a subunit is necessary for reconstituting active enzyme from separated subunits. 

Inhibitors of membrane fusion Inhibitors of integration of provirus Inhibitors of transcription provirus... 

BORK, P.M., SCHMITZ, M.L., KUHNT, M., ESCHER, C., HEINRICH, M Sesquiterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF-kappaB., FEBS Lett., 1997,402,85-90. 

Rifampicin was first shown by Hartmann et al. 54 to have a specific inhibitory effect on RNA polymerase from E. coli. Later, other active ansamycins were found and RNA polymerases from a large variety of bacteria other than E. coli proved to be sensitive to the drug. More recently, an RNA polymerase from E. coli containing only one subunit and probably involved in the initiation of DNA replication (dna G gene product) has been shown to be resistant to rifampicin5 s This holds true also for the various mammalian RNA polymerases. In contrast to non-specific inhibitors of transcription such as actinomycin and mitomycin, rifampicin interacts specifically with the bacterial enzyme itself. With the aid of 14C-labelled rifampicin it could be shown that the drug forms a very stable complex with the enzyme in a molar ratio of 1 1S6> 57 The dissociation constant of this complex is 10-9 M at 37 °C and... 

Some other recent work indicates an apparent qualitative effect on protein synthesis. Ho (31) and Jacobsen et al. (32) detected new peptides when aleurone layers were treated with ABA. These peptides turned over rapidly, and the quantities formed were reduced by inhibitors of transcription and translation. Little else is known currently about the peptides. 

There are also inhibitors that affect enzyme synthesis. Inhibitors of transcription (e.g., dibromothymoquinone [DBMIB]) and inhibitors of translation (e.g., cyclo-heximide [CHX]) are available but these are not specific to particular enzymes. In addition, because protein synthesis takes place within the chloroplast and mitochondrion in eukaryotes, prokaryotic protein synthesis inhibitors (e.g., chloramphenicol [CAP]) may be necessary to distinguish prokaryotic versus eukaryotic activity (e.g., Segovia and Berges, 2005). 

Antibiotic inhibitors of transcription Section 28,1.9 Burkitt lymphoma and B-cell leukemia Section 28,2.6... 

IkB-q (inhibitor of transcription factor NF-kB)), proteins that regulate cellular adaptation to hypoxic stress (i.e., HIF-lct), and proteins related to aberrant gene expression in tumors (e.g., c-Jun, /3-catenin, IttB-a, E2F1). Proteasome inhibitors are under development as new antitumor chemotherapeutic agents and the proteasome inhibitor bortezomib (PS-341, Velcade) has been approved by the U.S. Food and Drug Administration (FDA). 

This mode of regulation is negative, because the active regulatory element (the repressor) is an inhibitor of transcription. Positive control is also a factor, involving the CRP site shown in Figure 26.17. 

The increased rate of ABA biosynthesis in dehydrated leaves can be blocked by inhibitors of transcription, such as actinomycin D and cordycepin [163-165], as well as by cycloheximide, an inhibitor of cytoplasmic protein synthesis [163,165-167]. These results indicate that nuclear gene transcription and cytosolic protein synthesis are required before an increase in ABA biosynthesis can take place. These processes probably account for the lag period prior to ABA accumulation following the onset of stress [94,163]. Water stress and cycloheximide had no effect on the conversion of XAN to ABA [54]. This indicates that the enzymes catalyzing these conversions are constitutively expressed. The most likely step stimulated by dehydration is, therefore, at the level of xanthophyll cleavage, although isomerization of xanthophylls cannot be ruled out. 

Cell division was arrested with cytosine arabinoside to avoid the problem of receptor expression in the products of mitosis during the course of the experiment. It is quite apparent that resensitization of desensitized cells occurs in the absence of carbacyclin, and in further experiments (data not shown) the resensitization was shown to be dependent on de novo protein synthesis. There was no resensitization in the presence of cycloheximide or actinomycin D (an inhibitor of transcription). It is of particular significance that, when cells were desensitized and then allowed to resensitize, the synthesis of new receptor was accompanied by a restoration of the capacity for enzyme activation, and also by a return to the relatively high-affinity for enzyme stimulation (Figure 8.21). 

Transcription of DNA containing 6-thioguanine under photolytic conditions combine to eifectively irreversibly inhibit transcription by RNA pol II, possibly due to formation of guanine-6-sulfonate, which is a known inhibitor of transcription. The -functionalised thioguanine derivative (47) has been used to site-specifically modify the cytosine residue it is opposed to in duplex DNA. ... 

The effects of aldosterone are different. First, the onset of its effect takes at least one hour, while ADH takes only a few minutes. Aldosterone causes an increase in the density of channels [196,201,203] with no change in apparent affinity to amiloride. Thus, as far as the probe molecule is concerned, the new channels appear to be identical to the pre-existing channels. The effect of aldosterone on channel density is blocked by inhibitors of transcription and translation [196], indicating that de novo protein synthesis is involved in the effect. Whether the new protein is actually new channel or whether the new protein can expose pre-existing but occluded sites in the membrane has not been answered. 

Cannot be demonstrated with the purified enzymes it depends on the protein-synthesizing system of the cell. In whole cells derepression is prevented by inhibitors of transcription and translation, and by irthibi-tors of mrcleic acid and protein metabolism. 

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