Trichostatin A and Structurally Related Histone Deacetylase Inhibitors Induce 5-Lipoxygenase Promoter Activity
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N. Klan
Abstract
5-Lipoxygenase (5-LO) mRNA expression in Mono Mac 6 cells is induced by the histone deacetylase inhibitor trichostatin A (TsA). In order to study the effects of TsA and several structurally related compounds such as MD85, D237 and M232 on 5-LO promoter activity, we have analyzed the response of a 5-lipoxygenase (5-LO) promoter luciferase reporter gene construct to histone deacetylase inhibitors in transiently transfected Mono Mac 6 and HeLa cells. We show that the activity of 5-LO promoter constructs comprising the sequences -778 to +53 and of several successive deletions of the 5-LO promoter is strongly increased upon TsA treatment. The data suggest a significant involvement of histone deacetylases in the regulation of 5-LO gene transcription. The basal activity of the 5-LO promoter strongly depends on the presence of multiple Sp1-binding sites (GC-boxes), five of which are positioned in tandem. Deletion of the five tandemized GCboxes in the 5-LO reporter gene construct revealed that the induction of 5-LO promoter activity by TsA seems to be independent of these GCboxes. Methylation of 5-LO reporter gene constructs by M.HpaII reduced 5-LO promoter activity but did not prevent induction of promoter activity by TsA, although the activated reporter gene activities were lower compared to the unmethylated plasmid, indicating the dominance of methylation over TsA-sensitive histone deacetylation in silencing of the 5-LO gene. The structure-activity data obtained for histone deacetylase inhibitors suggest that this assay system might serve as a cellular screening tool for the development of HDAC inhibitors.
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- The Circadian Clock of the Unicellular Eukaryotic Model Organism Chlamydomonas reinhardtii
- Cardiovascular Control by the Suprachiasmatic Nucleus: Neural and Neuroendocrine Mechanisms in Human and Rat
- Synchronization of the Molecular Clockwork by Light- and Food-Related Cues in Mammals
- Identification of Rhythmic Subsystems in the Circadian Cycle of Crassulacean Acid Metabolism under Thermoperiodic Perturbations
- Age-Dependent Effects of Conditioning on Cholinergic and Vasopressin Systems in the Rat Suprachiasmatic Nucleus
- The Magnetofection Method: Using Magnetic Force to Enhance Gene Delivery
- The Protease Inhibitor Bikunin, a Novel Anti-Metastatic Agent
- Transcriptional Regulation of the Urokinase Receptor (u-PAR) – A Central Molecule of Invasion and Metastasis
- Identification and Characterization of KAT, a Novel Gene Preferentially Expressed in Several Human Cancer Cell Lines
- Trichostatin A and Structurally Related Histone Deacetylase Inhibitors Induce 5-Lipoxygenase Promoter Activity
- Treatment of Tumor Cells with Histone Deacetylase Inhibitors Results in Altered Recruitment of Methyl-CpG Binding Proteins to a Methylated CpG Island
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- Contribution of the Absolutely Conserved B8Gly to the Foldability of Insulin
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- Quantification of Elastase-Like Activity in 13 Human Cancer Cell Lines and in an Immortalized Human Epithelial Cell Line by RP-HPLC
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