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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 microM TSA and 1-10 mM butyrate for 1-2 days. Both of these inhibitors induced a prominent neuronal apoptosis characterized by morphological changes as well as by the activation of caspase-3 protease and subsequent cleavage of poly(ADP-ribose) polymerase, one of the caspase-3 targets. Caspase-3 activities reached the highest level on the second day after treatment, higher in the proliferating neuroblastoma cells than in the cerebellar granule neurons. Caspase-3 activation and morphological changes were prevented by cycloheximide treatment. Histone deacetylase inhibitors increased the DNA-binding activities of AP1, CREB and NF-kappaB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells.
Brain Res Mol Brain Res 1998 Oct 30
PMID:Neuronal apoptosis induced by histone deacetylase inhibitors. 979 19

Reversible acetylation of core histones plays an important role in transcriptional regulation, cell cycle progression and developmental events. The acetylation state of histones is controlled by a dynamic equilibrium between activities of histone acetylase and deacetylase enzymes. Histone deacetylase (HDAC) was recently suggested to be the target of a fungus-derived antiprotozoal agent exhibiting structural similarity to known HDAC inhibitors. We have initiated a study of HDAC of human malaria parasite, Plasmodium falciparum, to evaluate its potential as the target for novel antimalarials and its role in parasite development. We have isolated HDAC1 gene from the P. falciparum genomic and cDNA libraries. The nucleotide sequence contains no intervening sequence and its open reading frame (ORF) codes for a protein of 449 amino acid residues. We have named the protein, PfHDAC1, as the sequence shows significant homology to yeast, human and other eukaryotic HDACs. Northern blot analysis of the total RNA from different asexual and sexual stages of the parasite reveals the presence of single mRNA transcript, which is predominantly expressed in mature asexual blood stages and in gametocytes. Antiserum raised against a carboxyl terminal peptide immunoprecipitated an in vitro translated P. falciparum HDAC gene product and recognized an approximately 50 kDa protein in the Triton X-100 insoluble fraction of parasites. Immunoelectron microscopy analysis showed majority of the protein localized in the nucleus of P. falciparum. To our knowledge, this is the first HDAC gene isolated from the malaria parasite.
Mol Biochem Parasitol 1999 Mar 15
PMID:Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum. 1021 20

Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21(+/+) and p21(-/-) cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors.
Mol Pharmacol 2001 Oct
PMID:Up-regulation of p21(WAF1/CIP1) by histone deacetylase inhibitors reduces their cytotoxicity. 1156 46

Histone deacetylases (HDACs) play a key role in regulating eukaryotic gene expression. The HDAC domain, homologous to the yeast repressors RPD3 and HDA1, is considered necessary and sufficient for enzymatic activity. Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT. All experimental conditions leading to the suppression of HDAC4 binding to SMRT/N-CoR and to HDAC3 result in the loss of enzymatic activity associated with HDAC4. In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.
Mol Cell 2002 Jan
PMID:Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. 1180 85

Histone deacetylases (HDACs) are important for gene regulation and the maintenance of heterochromatin in eukaryotes. Schizosaccharomyces pombe was used as a model system to investigate the functional divergence within this conserved enzyme family. S. pombe has three HDACs encoded by the hda1(+), clr3(+), and clr6(+) genes. Strains mutated in these genes have previously been shown to display strikingly different phenotypes when assayed for viability, chromosome loss, and silencing. Here, conserved differences in the substrate binding pocket identify Clr6 and Hda1 as class I HDACs, while Clr3 belongs in the class II family. Furthermore, these HDACs were shown to have strikingly different subcellular localization patterns. Hda1 was localized to the cytoplasm, while most of Clr3 resided throughout the nucleus. Finally, Clr6 was localized exclusively on the chromosomes in a spotted pattern. Interestingly, Clr3, the only HDAC present in the nucleolus, was required for ribosomal DNA (rDNA) silencing. Clr3 presumably acts directly on heterochromatin, since it colocalized with the centromere, mating-type region, and rDNA as visualized by in situ hybridization. In addition, Clr3 could be cross-linked to mat3 in chromatin immunoprecipitation experiments. Western analysis of bulk histone preparations indicated that Hda1 (class I) had a generally low level of activity in vivo and Clr6 (class I) had a high level of activity and broad in vivo substrate specificity, whereas Clr3 (class II) displayed its main activity on acetylated lysine 14 of histone H3. Thus, the distinct functions of the S. pombe HDACs are likely explained by their distinct cellular localization and their different in vivo specificities.
Mol Cell Biol 2002 Apr
PMID:Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity. 1188 4

Histone deacetylase inhibitor (HDAI) induces accumulation of highly acetylated histones by inhibiting the activity of histone deacetylase and inhibits cell proliferation, induces differentiation, and promotes apoptosis. TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis in various human cancer cells, a promising observation because it raises the possibility of a death ligand selectively for tumor cells. However, resistance to TRAIL-induced apoptosis was seen in colonic adenocarcinoma cell lines. So we investigated whether human colonic adenocarcinoma cell lines can be sensitized to TRAIL-induced apoptosis by the addition of HDAI. We investigated sensitivity to histone deacetylase inhibitor in colonic adenocarcinoma cell lines using the MTT assay. Cell viability decreased with sodium butyrate (SB) and trichostatinA (TSA) in a dose-dependent manner in LS 180 and HT-29 cells. Nuclear condensation and fragmentation were observed by DAPI staining after 24 h stimulation with SB or TSA in LS 180 cells. We also investigated the combination of HDAI and TNF family members (TRAIL, anti-Fas antibody or TNFalpha) in colonic adenocarcinoma cell lines. HDAI augmented TNF family-related apoptosis in LS 180 cells and HT-29 cells. HDAI sensitizes human colonic adenocarcinoma cell lines to TRAIL-mediated apoptosis. HDAI may be useful as an adjuvant agent for TRAIL in the treatment of human colonic adenocarcinomas that are resistant to TRAIL.
Int J Mol Med 2002 May
PMID:Histone deacetylase inhibitors sensitize human colonic adenocarcinoma cell lines to TNF-related apoptosis inducing ligand-mediated apoptosis. 1195 60

Ovarian hormones have a pivotal role in the control of proliferation in the mammary gland, and cumulative life-time exposure to ovarian hormones is known to be a determinant of breast cancer risk. We have shown previously that a p.o.-active, long-acting butyrate analogue, sodium phenylbutyrate (PB), reduced proliferation in normal and malignant human breast cells in culture and reduced expression of ovarian hormone receptors, suggesting that PB had cellular effects consistent with decreasing breast cancer risk. The aim of this study was to determine the in vivo effects of PB in the normal mammary gland on epithelial cell proliferation, estrogen receptor alpha (ER alpha) expression, and cyclin D1 expression. BALB/c mice were treated with PB, delivered by mini-osmotic pumps, for 7 days. Moderate (250 mg/kg/day) and high (500 mg/kg/day) PB treatment resulted in a decrease in proliferation in mammary epithelial cells (P < 0.001), determined by bromodeoxyuridine incorporation. Analysis of ER alpha immunostaining revealed a significant reduction in moderate- and high-treatment groups (P = 0.01 and P = 0.02), and expression of cyclin D1 was virtually ablated (P < 0.001). Histone deacetylase inhibition is a known mechanism of butyrate action, and consistent with this, PB increased levels of acetylated histone H3 in the mammary gland. In summary, PB decreased proliferation in the mammary gland in vivo at clinically achievable doses. Decreased proliferation was accompanied by changes in the levels of ER alpha and cyclin D1. These data show that PB modulates parameters thought to be involved in the carcinogenic process in the normal mammary gland, and compounds in this class may therefore be useful candidates for breast cancer chemoprevention.
Mol Cancer Ther 2002 Oct
PMID:Cell proliferation in the normal mouse mammary gland and inhibition by phenylbutyrate. 1248 25

Histone deacetylase (HDAC) inhibitors have an unprecedented potential to occupy a major position in the future market of anticancer agents. However, progress in the development of these new chemotherapeutics is largely dependent on the existence of bioassays well-suited for inhibitor screening. Herein, we summarize recent developments in HDAC assay technology and, particularly, discuss different assay types with respect to their suitability for high-throughput screening programs.
Mol Genet Metab
PMID:Recent progress in the development of assays suited for histone deacetylase inhibitor screening. 1456 63

Histone deacetylase inhibitors induce hyperacetylation of the amino-terminal lysine residues of the core nucleosomal histones, which results in chromatin remodeling and altered gene expression. Present studies demonstrate that exposure to a novel hydroxamic acid analogue histone deacetylase inhibitor, LAQ824, induced p21WAF1 and p27KIP1 and caused growth arrest and apoptosis of human breast cancer SKBR-3 and BT-474 cells that possess amplification and overexpression of Her-2/neu. Treatment with LAQ824 depleted the mRNA and protein levels of Her-2/neu-encoded Her-2, which was associated with attenuation of pAKT, c-Raf-1, and phosphorylated mitogen-activated protein kinase levels. LAQ824 also induced the acetylation of heat shock protein (hsp) 90, resulting in inhibition of its binding to ATP, which has been shown to impair the chaperone association of hsp 90 with its client proteins, Her-2, AKT, and c-Raf-1. Consistent with this, treatment with LAQ824 shifted the binding of Her-2 from hsp 90 to hsp 70, promoting proteasomal degradation of Her-2. Thus, LAQ824 depletes Her-2 through two mechanisms: attenuation of its mRNA levels and promotion of its degradation by the proteasome. Following LAQ824 treatment, the cell membrane association, autotyrosine phosphorylation, and colocalization of Her-2 with HER-3 also declined. Cotreatment with LAQ824 significantly increased trastuzumab-induced apoptosis of BT-474 and SKBR-3 cells. This was associated with greater attenuation of Her-2, c-Raf-1, and pAKT levels. LAQ824 also enhanced taxotere-induced, epothilone B-induced, and gemcitabine-induced apoptosis of BT-474 and SKBR-3 cells. These findings suggest that LAQ824 is active against human breast cancer cells and has the potential to improve the efficacy of trastuzumab, taxotere, gemcitabine, and epothilone B against breast cancer with Her-2/neuamplification.
Mol Cancer Ther 2003 Oct
PMID:Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. 1457 62

Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation, or apoptosis in numerous cancer cell types both in vivo and in vitro. These dramatic effects are the result of a specific reprogramming of gene expression. However, the mechanism by which these agents activate the transcription of some genes, such as p21(WAF1), but repress others, such as cyclin D1, is currently unknown. We have been studying the human SRC gene as a model for HDI-mediated transcriptional repression. We found previously that both the tissue-specific and housekeeping SRC promoters were equally repressed by HDIs. Here we show that, despite an overt dissimilarity, both SRC promoters do share similar core promoter elements and transcription is TAF1 dependent. Detailed analysis of the SRC promoters suggested that both core and proximal promoter elements were responsible for HDI-mediated repression. This was confirmed in a series of promoter-swapping experiments with the HDI-inducible, TAF1-independent p21(WAF1) promoter. Remarkably, all the SRC-p21(WAF1) chimeric promoter constructs were not only repressed by HDIs but also dependent on TAF1. Together these experiments suggest that the overall promoter architecture, rather than discrete response elements, is responsible for HDI-mediated repression, and they implicate core promoter elements in particular as potential mediators of this response.
Mol Cell Biol 2004 Mar
PMID:SRC proximal and core promoter elements dictate TAF1 dependence and transcriptional repression by histone deacetylase inhibitors. 1499 69


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