Transcriptional activator inhibition

EGCG inhibits angiogenesis by enhancing FOXO transcriptional activity. Inhibition of AKT and MEK kinases synergisticaUy induced FOXO transcriptional activity, which was further enhanced in the presence of EGCG. Phosphorylation-deficient mutants of FOXO induced FOXO transcriptional activity and inhibited HUVEC cell migration and capillary tube formation. Inhibition of FOXO... 

Androgen receptor Transcriptional regulator Inhibition of androgen receptor transcriptional activity... 

ECE isoforms are also involved in the degradation of A 3 peptide. A genetic variant of ECE-1 with an increased transcriptional activity is associated with a decreased risk for AD. Thus, the inhibition of ECE in the CNS may increase the risk for the development of Alzheimer s disease (AD). 

Vickers T.A., Grieeity M.G., Ramasamy K, Risen L.M., Freier S.M. Inhibition of NF-kB specific transcriptional activation by PNA strand invasion. Nucleic Acids Res. 1995 23 3003-3008. 

Tibaduiza, E.C. et al., Excentric cleavage products of beta-carotene inhibit estrogen receptor positive and negative breast tumor cell growth in vitro and inhibit activator protein-1-mediated transcriptional activation, J. Nutr., 132, 1368, 2002. 

Shumilla, A.J., Broderick, J.R., Wang, Y., and Barchowsky, A., Chromium Cr(VI) inhibits the transcriptional activity of nuclear factor B by decreasing the interaction of p65 with cAMP-responsive elementbinding protein, Journal of Biological Chemistry, 274 (51), 36207-36212, 1999. 

Stimulation of a cell by first messengers that increase cellular Ca2+ concentrations similarly activates CREB (Fig. 23-9). This appears to occur via the phosphorylation of CREB on serine 133 by a CaMK, probably CaMKIV as well as, possibly, CaMKI. It remains to be established whether the activated kinase translocates to the nucleus, by analogy with the catalytic subunit of the cAMP kinase, or whether elevated Ca2+ signals enter the nucleus and activate the kinase already there. Interestingly, phosphorylation of CREB on a distinct serine residue, serine 142, by CaMKII appears to inhibit the transcriptional activity of CREB in vitro, although whether this inhibitory effect occurs in vivo is unknown. 

Platelet-activating factor is a transcriptional activator of cyclooxygenase-2. PAF induces mouse COX-2-promoter-driven luciferase activity transfected in neuroblastoma cells, such as NG108-15 or SH-SY5Y, and in NIH 3T3 cells (Fig. 33-5). The intracellular PAF antagonist BN 50730 inhibits PAF activation of this construct [41]. 

Tretinoin can reduce ACTH secretion through inhibition of transcriptional activities. Its use has been limited to animal models, and efficacy in humans is undetermined. 

The formation of a transcriptionally active complex requires the interaction of all transcription cofactors with their respective specific DNA sequences. Once they have bound to their specific sequences, it is on these that the remaining elements of the complex that do not interact directly with the DNA are assembled (Chin 1995 Filardo 2002). The elements of the complex that do not come into direct contact with DNA have their own specificity of interaction with the remaining proteins of the complex. Therefore, they include important restrictions so that a fully active transcriptional complex can be assembled with difficulty on a receptor dimer that has incorrectly recognized a HRE. Indeed, an incorrect interaction can imply a noticeable degree of transcription inhibition. 

Recently, a Japanese research group published preclinical safety and efficacy data of an oral antiestrogen (TZE-5323) (Saito et al. 2003). This drug has been shown to have a strong affinity for human ERa and ER/i and a dose-dependent capacity to inhibit estradiol-stimulated transcriptional activation (Saito et al. 2003). In the experimental endometriosis model in rats, TZE-5323 dose-dependently reduced the volume of the endometrial implant with an effectiveness similar to that of danazol and leuprorelin acetate without causing significant changes in bone mineral density and in serum estradiol levels (Saito et al. 2003). 

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