Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylase inhibitor-induced expression of p21WAF1 is p53 independent. In the present study, we provide evidence that trichostatin A (TSA), a specific inhibitor of histone deacetylase, can elevate H3 and H4 acetylation and p21WAF1 expression in NIH3T3 cells at first. To identify the transcription factor which is responsible for histone deacetylase inhibitor-induced expression of p21WAF1 and understand the potential events occurred during this process, we analyze the response of the mouse p21WAF1 promoter to TSA in detail. The region responsive to TSA treatment in the p21 promoter is located -100 bp upstream from transcription initiation site and contains a GC-box. The mutation introduced into this GC-box decreases most of the basal and TSA-induced promoter activity. The results from gel-shift assay show that Sp1 and Sp3 bind to this GC-rich region. Cotransfection with Sp1 and/or Sp3 expression constructs elevate both basal and induced promoter activity, and this elevation is dependent on the present of the GC-box. By contrast, cotransfection with reverse oriented Sp1 or Sp3 cDNA decreased basal and induced-promoter activity, as well as GC-box dependency. These findings provide physical and functional evidence which strongly indicated that both Sp1 and Sp3 are responsible for TSA-induced transactivation of the murine p21WAF1 promoter in NIH3T3 cells.
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PMID:Both Sp1 and Sp3 are responsible for p21waf1 promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells. 1032 29

Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. HDAC inhibition causes acetylated nuclear histones to accumulate in both tumor and normal tissues, providing a surrogate marker for the biological activity of HDAC inhibitors in vivo. The effects of HDAC inhibitors on gene expression are highly selective, leading to transcriptional activation of certain genes such as the cyclin-dependent kinase inhibitor p21WAF1/CIP1 but repression of others. HDAC inhibition not only results in acetylation of histones but also transcription factors such as p53, GATA-1 and estrogen receptor-alpha. The functional significance of acetylation of non-histone proteins and the precise mechanisms whereby HDAC inhibitors induce tumor cell growth arrest, differentiation and/or apoptosis are currently the focus of intensive research. Several HDAC inhibitors have shown impressive antitumor activity in vivo with remarkably little toxicity in preclinical studies and are currently in phase I clinical trial. The focus of this review is the development and clinical application of HDAC inhibitors for the treatment of cancer.
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PMID:Histone deacetylase inhibitors in cancer treatment. 1191 36

Histone deacetylase activity is potently inhibited by hydroaximc acid derivatives such as suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). These inhibitors specifically induce differentiation/apoptosis of transformed cells in vitro and suppress tumor growth in vivo. Because of its low toxicity, SAHA is currently evaluated in clinical trials for the treatment of cancer. SAHA and TSA induce apoptosis, which is characterized by mitochondrial stress, but so far, the critical elements of this apoptotic program remain poorly defined. To characterize in more detail this apoptotic program, we used human cell lines containing alterations in important elements of apoptotic response such as: p53, Bcl-2, caspase-9, and caspase-3. We demonstrate that caspase-9 is critical for apoptosis induced by SAHA and TSA and that efficient proteolytic activation of caspase-2, caspase-8, and caspase-7 strictly depends on caspase-9. Bcl-2 efficiently antagonizes cytochrome c release and apoptosis in response to both histone deacetylase inhibitors. We provide evidences that translocation into the mitochondria of the Bcl-2 family member Bid depends on caspase-9 and that this translocation is a late event during TSA-induced apoptosis. We also demonstrate that the susceptibility to TSA- and SAHA-induced cell death is regulated by p53.
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PMID:Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA). 1255 48

Histone deacetylase (HDAC) inhibitors cause growth arrest at the G1 and/or G2/M phases, and induce differentiation and/or apoptosis in a wide variety of tumour cells. The growth arrest at G1 phase by HDAC inhibitors is thought to be highly dependent on the upregulation of p21/WAF1, but the precise mechanism by which HDAC inhibitors cause G2/M arrest or apoptosis in tumour cells is unknown. Gadd45 causes cell cycle arrest at the G2/M phase transition and participates in genotoxic stress-induced apoptosis. We show here that it is also induced by a typical HDAC inhibitor, trichostatin A (TSA), through its promoter, in a p53-independent manner. To identify the mechanism of activation of the gadd45 promoter, we performed luciferase reporter analyses and electrophoretic mobility shift assays. These revealed that both the Oct-1 and CCAAT sites are needed for the full activation by TSA. We also found that the transcription factors Oct-1 and NF-Y specifically bind to each site. Thus, HDAC inhibitors can induce Gadd45 through its promoter without the need for functional p53, and both the Oct-1 and NF-Y concertedly participate in TSA-induced activation of the gadd45 promoter.
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PMID:p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y. 1458 2

Histone deacetylase inhibitors (HDACs) are known to exhibit antiproliferative effects on various carcinoma cells. In this study, the in vivo efficiency of two HDACs, sodium butyrate and tributyrin, on prostate cancer growth inhibition were investigated. To gain an insight into the possible underlying pathways, cell culture experiments were performed focusing on the expression of p21, Rb and c-myc. For in vivo testing, prostate cancer cell lines (PC3 and TSU-Pr1) were seeded on the chorioallantois membrane (CAM) and implanted in a xenograft model using nude mice. Standard Western blot analysis was performed for protein expression of p21, Rb and c-myc in HDAC-treated vs untreated prostate cancer cells. Both sodium butyrate and tributyrin had a considerable treatment effect on microtumours on the chicken egg at already very low concentrations of 0.1 mM. Tributyrin-treated tumours showed the strongest effect with 38% apoptotic nuclei in the prostate cancer cell line PC3. In the mouse model, there was almost no difference between sodium butyrate and tributyrin. In untreated animals the tumours were almost double the size 4 weeks after implantation. Tumours of the treatment groups had a significantly lower percentage of Ki-67-positive-stained nuclei. As demonstrated by Western blot analysis, these effects seem to be independent of p53 status and a pathway via p21-Rb-c-myc is possibly involved. In this study we have demonstrated a substantial in vivo treatment effect, which can be induced by the application of sodium butyrate or the orally applicable tributyrin in human prostate cancer. The given results may provide the rationale to apply these drugs in well-controlled clinical trials in patients being at high risk of recurrence after specific therapy or in patients with locally or distant advanced prostate cancer.
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PMID:Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer. 1473 5

The histone deacetylase inhibitors are a new class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription. Histone deacetylase inhibition induces the accumulation of hyperacetyl-ated nucleosome core histones in most regions of chromatin but affects the expression of only a small subset of genes, leading to transcriptional activation of some genes, but repression of an equal or larger number of other genes. Non-histone proteins such as transcription factors are also targets for acetylation with varying functional effects. Ace-tylation enhances the activity of some transcription factors such as the tumor suppressor p53 and the erythroid differentiation factor GATA-1 but may repress transcriptional activity of others including T cell factor and the co-activator ACTR. Recent studies in our laboratory and others have shown that the estrogen receptor alpha (ERalpha) can be hyperacetylated in response to histone deacetylase inhibition, suppressing ligand sensitivity and regulating transcriptional activation by histone deacetylase inhibitors. Conservation of the acetylated ERalpha motif in other nuclear receptors suggests that acetylation may play an important regulatory role in diverse nuclear receptor signaling functions. A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. Several compounds are currently in early phase clinical development as potential treatments for solid and hematological cancers both as monotherapy and in combination with cytotoxics and differentiation agents. This report reviews the biology and clinical development of histone deacetylase inhibitors for cancer therapy.
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PMID:Targeted histone deacetylase inhibition for cancer therapy. 1503 70

Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (deltapsim). Loss of deltapsim was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependent degradation of the pocket proteins pRb, p107 and p130, releasing 'free' E2F-1 following initial G1 arrest. Inhibition of proteasomal proteolysis, but not of caspase activity rescued pRb from degradation and functionally restored its inhibitory effect on the cyclin E gene, known to be suppressed by pRb-E2F-1 in conjunction with HDAC1. Using siRNA targeted against p53, E2F-1 still triggered apoptosis by inducing the E2F-responsive proapoptotic alpha- and beta-isoforms of p73. These data may determine future therapeutic strategies in which HDAC inhibitors can effectively eliminate HPV-positive cells by an apoptotic route that does not rely on the reactivation of the 'classical' p53 pathway through a preceding shut-off of viral gene expression.
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PMID:HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway. 1507 64

Histone deacetylases (HDACs) were originally identified as nuclear enzymes involved in gene transcription regulation. Until recently, it was thought that their activity was restricted within the nucleus, with histones as unique substrates. The demonstration that specific HDACs deacetylate nonhistone proteins, such as p53 and alpha-tubulin, broadened the field of activity of these enzymes. HDAC8, a class I HDAC, is considered to be ubiquitously expressed, as suggested by results of Northern blots performed on tissue RNA extracts, and transfection experiments using various cell lines have indicated that this enzyme may display a prominent nuclear localization. Using immunohistochemistry, we unexpectedly found that, in normal human tissues, HDAC8 is exclusively expressed by cells showing smooth muscle differentiation, including visceral and vascular smooth muscle cells, myoepithelial cells, and myofibroblasts, and is mainly detected in their cytosol. These findings were confirmed in vitro by nucleo-cytoplasmic fractionation and immunoblot experiments performed on human primary smooth muscle cells, and by the cytosolic detection of epitope-tagged HDAC8 overexpressed in fibroblasts. Immunocytochemistry strongly suggested a cytoskeleton-like distribution of the enzyme. Further double-immunofluorescence staining experiments coupled with confocal microscopy analysis showed that epitope-tagged HDAC8 overexpressed in murine fibroblasts formed cytoplasmic stress fiber-like structures that co-localized with the smooth muscle cytoskeleton protein smooth muscle alpha-actin. Our works represent the first demonstration of the restricted expression of a class I HDAC to a specific cell type and indicate that HDAC8, besides being a novel marker of smooth muscle differentiation, may play a role in the biology of these contractile cells.
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PMID:Expression of histone deacetylase 8, a class I histone deacetylase, is restricted to cells showing smooth muscle differentiation in normal human tissues. 1527 29

The tumor suppressor protein p53 is a transcription factor that regulates the response to cellular insults such as DNA damage and growth factor withdrawal. Transcriptional activity of p53 requires post-translational modification by phosphorylation and acetylation. This study used site-specific antibodies to demonstrate that nerve growth factor (NGF) treatment of PC12 cells results in p53 deacetylation at lysine (Lys) 382. Histone deacetylase (HDAC) activity, measured by a direct fluorescent assay, was increased after NGF treatment and peaked before p53 deacetylation. Inhibition of HDAC by trichostatin blocked the deacetylation of p53 and its transcriptional activity toward a reporter gene construct. Comparison of PC12 with PC12 cells containing a temperature-sensitive, dominant-negative construct showed that p53 deacetylation required functional p53. Inhibitors of MAP kinase that block p53 transactivation and inhibitors of TrkA receptor also abolished HDAC activation, indicating that deacetylation of p53 is an NGF-dependent post-translational mechanism of p53 activation. Finally, NGF or serum withdrawal did not lead to p53 deacetylation. A model is proposed in which the acetylation status of Lys 382 of p53 discriminates between cell cycle arrest and apoptosis.
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PMID:Deacetylation of p53 after nerve growth factor treatment in PC12 cells as a post-translational modification mechanism of neurotrophin-induced tumor suppressor activation. 1536 54

Histone deacetylase (HDAC) inhibitors have shown promise in clinical cancer therapy and to consistently induce p21WAF1/CIP1 expression in a p53-independent manner and via increased acetylation of the chromatin at the Sp1 sites in the p21WAF1/CIP1 promoter region. However, the exact mechanism by which HDAC inhibitors induce p21WAF1/CIP1 remains unclear. In this study, we observed that Trichostatin A (TSA), a HDAC inhibitor, induced strikingly p21WAF1/CIP1 expression in human cervical cancer (HeLa) cells, and this induction correlated with downregulation of c-myc expression. Coincident with this observation, knock down of c-myc with a c-myc specific small interfering RNA dramatically induced expression of p21WAF1/CIP1 in these cancer cells. These data suggest that c-myc may play a critical role in repression of p21WAF1/CIP1 expression in HeLa cells. More importantly, using chromatin immunoprecipitation assay, we observed for the first time that c-myc bound to the endogenous p21WAF1/CIP1 promoter in untreated HeLa cells, but not in TSA-treated cells. Taken together, TSA induced c-myc downregulation and release from the endogenous p21WAF1/CIP1 promoter contributes, at least partially, to transcriptional activation of the p21WAF1/CIP1 in HeLa cells.
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PMID:Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells. 1547 7


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