[show abstract][hide abstract] ABSTRACT: We have previously reported that ergolide, a sesquiterpene lactone isolated from Inula britannica, suppresses inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression by inhibiting nuclear factor-kappaB (NF-kappaB) in RAW 264.7 macrophages. In this study, we show that ergolide suppresses the DNA binding activity of NF-kappaB and nuclear translocation of NF-kappaB p65 subunit, leading to the inhibition of NF-kappaB-dependent gene transcription in 12-O-tetradecanoylphorbol 13acetate (TPA)-stimulated HeLa cells. We also show that ergolide decreases the degradation and phosphorylation of IkappaB, an inhibitory protein of NF-kappaB, and this effect is accompanied by a simultaneous reduction of IkappaB kinase (IKK) activity. However, ergolide does not inhibit in-vitro IKK activity directly, suggesting the possible involvement of upstream IKK kinases in the regulation of NF-kappaB activation. Furthermore, ergolide-mediated protein kinase Calpha (PKCalpha) inhibition is involved in reduction of NF-kappaB inhibition, as demonstrated by the observation that dominant negative PKCalpha, but not p44/42 MAPK and p38 MAPK, inhibits TPA-stimulated reporter gene expression. Taken together, our results suggest that ergolide suppresses NF-kappaB activation through the inhibition of PKCalpha-IKK activity, providing insight for PKCalpha as a molecular target for anti-inflammatory drugs.
Journal of Pharmacy and Pharmacology 05/2007; 59(4):561-6. · 2.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: We show that a histone deacetylase (HDAC) inhibitor apicidin increases the transcriptional activity of cyclin E gene, which results in accumulation of cyclin E mRNA and protein in a time- and dose-dependent manner. Interestingly, apicidin induction of cyclin E gene is found to be mediated by Sp1- rather than E2F-binding sites in the cyclin E promoter, as evidenced by the fact that specific inhibition of Sp1 leads to a decrease in apicidin activation of cyclin E promoter activity and protein expression, but mutation of E2F-binding sites of cyclin E promoter region fails to inhibit the ability of apicidin to activate cyclin E transcription. In addition, this transcriptional activation of cyclin E by apicidin is associated with histone hyperacetylation of cyclin E promoter region containing Sp1-binding sites. Our results demonstrate that regulation of histone modification by an HDAC inhibitor apicidin contributes to induction of cyclin E expression and this effect is Sp1-dependent.
Biochemical and Biophysical Research Communications 05/2006; 342(4):1168-73. · 2.41 Impact Factor