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Cytoplasmic IkappaBalpha increases NF-kappaB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3 总被引:1,自引:0,他引:1
Viatour P Legrand-Poels S van Lint C Warnier M Merville MP Gielen J Piette J Bours V Chariot A 《The Journal of biological chemistry》2003,278(47):46541-46548
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Organization of the genome is critical for maintaining cell-specific gene expression, ensuring proper cell function. It is well established that the nuclear lamina preferentially associates with repressed chromatin. However, the molecular mechanisms underlying repressive chromatin formation and maintenance at the nuclear lamina remain poorly understood. Here we show that emerin binds directly to HDAC3, the catalytic subunit of the nuclear co-repressor (NCoR) complex, and recruits HDAC3 to the nuclear periphery. Emerin binding stimulated the catalytic activity of HDAC3, and emerin-null cells exhibit increased H4K5 acetylation, which is the preferred target of the NCoR complex. Emerin-null cells exhibit an epigenetic signature similar to that seen in HDAC3-null cells. Emerin-null cells also had significantly less HDAC3 at the nuclear lamina. Collectively, these data support a model whereby emerin facilitates repressive chromatin formation at the nuclear periphery by increasing the catalytic activity of HDAC3. 相似文献
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Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3 总被引:1,自引:0,他引:1 下载免费PDF全文
Zhang X Wharton W Yuan Z Tsai SC Olashaw N Seto E 《Molecular and cellular biology》2004,24(12):5106-5118
Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding growth-differentiation factor 11 (Gdf11), a transforming growth factor beta family member that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression. 相似文献
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The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression 总被引:1,自引:0,他引:1 下载免费PDF全文
Regulation of NF-kappaB transactivation function is controlled at several levels, including interactions with coactivator proteins. Here we show that the transactivation function of NF-kappaB is also regulated through interaction of the p65 (RelA) subunit with histone deacetylase (HDAC) corepressor proteins. Our results show that inhibition of HDAC activity with trichostatin A (TSA) results in an increase in both basal and induced expression of an integrated NF-kappaB-dependent reporter gene. Chromatin immunoprecipitation (ChIP) assays show that TSA treatment causes hyperacetylation of the wild-type integrated NF-kappaB-dependent reporter but not of a mutant version in which the NF-kappaB binding sites were mutated. Expression of HDAC1 and HDAC2 repressed tumor necrosis factor (TNF)-induced NF-kappaB-dependent gene expression. Consistent with this, we show that HDAC1 and HDAC2 target NF-kappaB through a direct association of HDAC1 with the Rel homology domain of p65. HDAC2 does not interact with NF-kappaB directly but can regulate NF-kappaB activity through its association with HDAC1. Finally, we show that inhibition of HDAC activity with TSA causes an increase in both basal and TNF-induced expression of the NF-kappaB-regulated interleukin-8 (IL-8) gene. Similar to the wild-type integrated NF-kappaB-dependent reporter, ChIP assays showed that TSA treatment resulted in hyperacetylation of the IL-8 promoter. These data indicate that the transactivation function of NF-kappaB is regulated in part through its association with HDAC corepressor proteins. Moreover, it suggests that the association of NF-kappaB with the HDAC1 and HDAC2 corepressor proteins functions to repress expression of NF-kappaB-regulated genes as well as to control the induced level of expression of these genes. 相似文献
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Ka Yang Yanling Song Haibo Xie Hao Wu Yi-Ting Wu Eric D. Leisten Weiping Tang 《Bioorganic & medicinal chemistry letters》2018,28(14):2493-2497
Histone deacetylases (HDACs) decrease the acetylation level of histones and other non-histone proteins. Over expression of HDACs have been observed in cancers and other diseases. Targeted protein degradation by “hijacking” the natural ubiquitin-proteasome-system (UPS) recently emerged as a novel technology to “knock-out” endogenous disease-causing proteins. We applied this strategy to the development of the first small molecule degraders for zinc-dependent HDACs by conjugating non-selective HDAC inhibitors with E3 ubiquitin ligase ligands. Through cell-based assays, we discovered novel bifunctional molecules (dHDAC6) that could selectively degrade HDAC6. Further mechanistic studies indicated that HDAC6 was selectively removed by the UPS. 相似文献
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Lee S Shinji C Ogura K Shimizu M Maeda S Sato M Yoshida M Hashimoto Y Miyachi H 《Bioorganic & medicinal chemistry letters》2007,17(17):4895-4900
We designed and synthesized hydroxamic acid derivatives bearing a 4-(3-pyridyl)phenyl group as a cap structure, and found that they exhibit potent histone deacetylase (HDAC) inhibitory activity. A representative compound, 17a, showed more potent growth-inhibitory activity against pancreatic cancer cells and greater upregulation of p21(WAF1/CIP1) expression than the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (Zolinza). 相似文献
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The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds. 总被引:19,自引:3,他引:16 下载免费PDF全文
Y Kanno C A Kozak C Schindler P H Driggers D L Ennist S L Gleason J E Darnell Jr K Ozato 《Molecular and cellular biology》1993,13(7):3951-3963
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Methot JL Chakravarty PK Chenard M Close J Cruz JC Dahlberg WK Fleming J Hamblett CL Hamill JE Harrington P Harsch A Heidebrecht R Hughes B Jung J Kenific CM Kral AM Meinke PT Middleton RE Ozerova N Sloman DL Stanton MG Szewczak AA Tyagarajan S Witter DJ Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2008,18(3):973-978
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain. 相似文献
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Pathological cardiac hypertrophy is a classical hallmark of heart failure. At the molecular level, inhibition of histone deacetylase (HDAC) enzymes attenuate pathological cardiac hypertrophy in vitro and in vivo. Emodin is an anthraquinone that has been implicated in cardiac protection. However, it is not known if the cardio-protective actions for emodin are mediated through HDAC-dependent regulation of gene expression. Therefore, we hypothesized that emodin would attenuate pathological cardiac hypertrophy via inhibition of HDACs, and that these actions would be reflected in an emodin-rich food like rhubarb. In this study, we demonstrate that emodin and Turkish rhubarb containing emodin inhibit HDAC activity in vitro, with fast-on, slow-off kinetics. Moreover, we show that emodin increased histone acetylation in cardiomyocytes concomitant to global changes in gene expression; gene expression changes were similar to the well-established pan-HDAC inhibitor trichostatin A (TSA). We additionally present evidence that emodin inhibited phenylephrine (PE) and phorbol myristate acetate (PMA)-induced hypertrophy in neonatal rat ventricular myocytes (NRVMs). Lastly, we demonstrate that the cardioprotective actions of emodin are translated to an angiotensin II (Ang) mouse model of cardiac hypertrophy and fibrosis and are linked to HDAC inhibition. These data suggest that emodin blocked pathological cardiac hypertrophy, in part, by inhibiting HDAC-dependent gene expression changes. 相似文献
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Chen PC Patil V Guerrant W Green P Oyelere AK 《Bioorganic & medicinal chemistry》2008,16(9):4839-4853
Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. Small molecule HDAC inhibitors identified so far fall in to three distinct structural motifs: the zinc-binding group (ZBG), a hydrophobic linker, and a recognition cap group. Here we report the suitability of a 1,2,3-triazole ring as a surface recognition cap group-linking moiety in suberoylanilide hydroxamic acid-like (SAHA-like) HDAC inhibitors. Using “click” chemistry (Huisgen cycloaddition reaction), several triazole-linked SAHA-like hydroxamates were synthesized. Structure–activity relationship revealed that the position of the triazole moiety as well as the identity of the cap group markedly affected the in vitro HDAC inhibition and cell growth inhibitory activities of this class of compounds. 相似文献
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Bhadaliya Chetan Mahesh Bunha Monika Jagrat Barij Nayan Sinha Philipp Saiko Geraldine Graser Thomas Szekeres Ganapathy Raman Praveen Rajendran Dhatchana Moorthy Arijit Basu Venkatesan Jayaprakash 《Bioorganic & medicinal chemistry letters》2010,20(13):3906-3910
Six compounds were synthesized with piperazine in linker region and hydroxamate as Zinc Binding Group (ZBG). They were screened against three cancer cell-lines (NCIH460; HCT116; U251). Compounds 5c and 5f with GI50 value of 9.33 ± 1.3 μM and 12.03 ± 4 μM, respectively, were tested for their inhibitory potential on hHDAC8. Compound 5c had IC50 of 33.67 μM. Compounds were also screened for their anticancer activity against HL60 human promyelocytic leukemia cell line due to the presence of pharmacophoric features of RR inhibitors in them. Compound 5c had IC50 of 0.6 μM at 48 h. 相似文献
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Synthesis, enzymatic inhibition, and cancer cell growth inhibition of novel delta-lactam-based histone deacetylase (HDAC) inhibitors 总被引:1,自引:0,他引:1
Kim HM Lee K Park BW Ryu DK Kim K Lee CW Park SK Han JW Lee HY Lee HY Han G 《Bioorganic & medicinal chemistry letters》2006,16(15):4068-4070
delta-Lactam-based hydroxamic acids, inhibitors of histone deacetylase (HDAC), have been synthesized via ring closure metathesis of key diene intermediates followed by conversion to hydroxamic acid analogues. The hydroxamic acids 12a, 12b, and 17c showed potent inhibitory activity in HDAC enzyme assay. The hydroxamic acid 12b exhibited growth inhibitory activity on five human tumor cell lines, showing good sensitivity on the MDA-MB-231 breast tumor cell. 相似文献