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组蛋白去乙酰化酶 6(HDAC6)是组蛋白去乙酰化酶(HDACs)IIb 家族中的一员,主要催化 α- 微管蛋白、热休克蛋白 Hsp90、皮质肌动蛋白及过氧化物还原酶等的去乙酰化。HDAC6 与肿瘤、神经退行性疾病、炎症、自身免疫应答、细菌感染及心脏病等 诸多疾病的病理生理进程密切相关,是一个极具应用前景的药物靶标。选择性 HDAC6 抑制剂是目前该领域的研究热点,有望克服广谱 HDAC 抑制剂存在的选择性差、副作用大等缺点。综述 HDAC6 的结构、生化功能、与疾病的关系及其选择性抑制剂的研究进展,为开发 新型选择性 HDAC6 抑制剂提供参考。 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(21):2430-2435
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《Cell cycle (Georgetown, Tex.)》2013,12(5):450-451
Commentary to:An Intact NF-κB Pathway is Required for Histone Deacetylase Inhibitor-Induced G1 Arrest and Maturation in Human Myeloid Leukemia (U937)Yun Dai, Mohamed Rahmani, Steven Grant 相似文献
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DNA双链断裂(double strand breaks, DSBs)对细胞生存是致命的.细胞内非同源末端连接(NHEJ)、重组修复(HDR)、单链退火修复(SSA)和微同源序列末端连接(MMEJ)等通路可竞争性修复DNA双链断裂损伤.在肿瘤细胞DNA中制造难以修复的基因损伤,诱导肿瘤细胞周期中止、坏死和凋亡是临床放、化疗的主要策略.组蛋白去乙酰化酶(histone deacetylase)作为抗肿瘤治疗的新靶标,其抑制剂(histonedeacetylase inhibitors, HDACi)可显著降低肿瘤细胞DSBs修复能力,增强肿瘤细胞的放、化疗敏感性.研究显示,HDACi抑制了肿瘤细胞中具有正确修复倾向的HDR和经典NHEJ通路,具有错误修复倾向的SSA和MMEJ路径也可能牵涉其中.目前,HDACi作用于DSBs修复通路的分子机制已取得较大进展,但仍有许多问题有待阐明. 相似文献
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组蛋白去乙酰化酶抑制剂(HDACi)是一类新的化疗药物,能够有效抑制组蛋白去乙酰化酶的活性,促进组蛋白及非组蛋白的乙酰化修饰,在转录和翻译后修饰水平调控肿瘤靶蛋白及凋亡相关蛋白的表达和降解,活化凋亡信号通路,诱导肿瘤细胞凋亡。HDACi抑制抗氧化蛋白的表达,提高细胞内活性氧的水平,引起细胞的氧化损伤。因此,氧化损伤诱导的细胞凋亡也是HDACi杀伤肿瘤细胞的重要机制。HDACi诱导细胞凋亡机制的发现将进一步促进HDACi在临床治疗中的应用。 相似文献
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Sascha Venturelli Regina G. Belz Andreas K?mper Alexander Berger Kyra von Horn André Wegner Alexander B?cker Gérald Zabulon Tobias Langenecker Oliver Kohlbacher Fredy Barneche Detlef Weigel Ulrich M. Lauer Michael Bitzer Claude Becker 《The Plant cell》2015,27(11):3175-3189
To secure their access to water, light, and nutrients, many plant species have developed allelopathic strategies to suppress competitors. To this end, they release into the rhizosphere phytotoxic substances that inhibit the germination and growth of neighbors. Despite the importance of allelopathy in shaping natural plant communities and for agricultural production, the underlying molecular mechanisms are largely unknown. Here, we report that allelochemicals derived from the common class of cyclic hydroxamic acid root exudates directly affect the chromatin-modifying machinery in Arabidopsis thaliana. These allelochemicals inhibit histone deacetylases both in vitro and in vivo and exert their activity through locus-specific alterations of histone acetylation and associated gene expression. Our multilevel analysis collectively shows how plant-plant interactions interfere with a fundamental cellular process, histone acetylation, by targeting an evolutionarily highly conserved class of enzymes. 相似文献
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Richard Brad Jones Rachel O'Connor Stefanie Mueller Maria Foley Gregory L. Szeto Dan Karel Mathias Lichterfeld Colin Kovacs Mario A. Ostrowski Alicja Trocha Darrell J. Irvine Bruce D. Walker 《PLoS pathogens》2014,10(8)
Resting memory CD4+ T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia. 相似文献
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Terra Vleeshouwer-Neumann Michael Phelps Theo K. Bammler James W. MacDonald Isaac Jenkins Eleanor Y. Chen 《PloS one》2015,10(12)
Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs) in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP) studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients. 相似文献
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Francesco Spallotta Silvia Tardivo Simona Nanni Jessica D. Rosati Stefania Straino Antonello Mai Matteo Vecellio Sergio Valente Maurizio C. Capogrossi Antonella Farsetti Julie Martone Irene Bozzoni Alfredo Pontecorvi Carlo Gaetano Claudia Colussi 《The Journal of biological chemistry》2013,288(32):22915-22929
Histone deacetylase inhibitors (DIs) are promising drugs for the treatment of several pathologies including ischemic and failing heart where they demonstrated efficacy. However, adverse side effects and cardiotoxicity have also been reported. Remarkably, no information is available about the effect of DIs during tissue regeneration following acute peripheral ischemia. In this study, mice made ischemic by femoral artery excision were injected with the DIs MS275 and MC1568, selective for class I and IIa histone deacetylases (HDACs), respectively. In untreated mice, soon after damage, class IIa HDAC phosphorylation and nuclear export occurred, paralleled by dystrophin and neuronal nitric-oxide synthase (nNOS) down-regulation and decreased protein phosphatase 2A activity. Between 14 and 21 days after ischemia, dystrophin and nNOS levels recovered, and class IIa HDACs relocalized to the nucleus. In this condition, the MC1568 compound increased the number of newly formed muscle fibers but delayed their terminal differentiation, whereas MS275 abolished the early onset of the regeneration process determining atrophy and fibrosis. The selective DIs had differential effects on the vascular compartment: MC1568 increased arteriogenesis whereas MS275 inhibited it. Capillarogenesis did not change. Chromatin immunoprecipitations revealed that class IIa HDAC complexes bind promoters of proliferation-associated genes and of class I HDAC1 and 2, highlighting a hierarchical control between class II and I HDACs during tissue regeneration. Our findings indicate that class-selective DIs interfere with normal mouse ischemic hindlimb regeneration and suggest that their use could be limited by alteration of the regeneration process in peripheral ischemic tissues. 相似文献
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Elizabeth A. Thomas 《Molecular neurobiology》2009,40(1):33-45
Histone deacetylase (HDAC) inhibitors represent a promising new avenue of therapeutic options for a range of neurological
disorders. Within any particular neurological disorder, neuronal damage or death is not widespread; rather, particular brain
regions are preferentially affected. Different disorders exhibit distinct focal pathologies. Hence, understanding the region-specific
effects of HDAC inhibitors is essential for targeting appropriate brain areas and reducing toxicity in unaffected areas. The
outcome of HDAC inhibition depends on several factors, including the diversity in the central nervous system expression of
HDAC enzymes, selectivity of a given HDAC inhibitor for different HDAC enzymes, and the presence or absence of cofactors necessary
for enzyme function. This review will summarize brain regions associated with various neurological disorders and factors affecting
the consequences of HDAC inhibition. 相似文献
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Wolfgang Link Julen Oyarzabal Beatriz G. Serelde Maria Isabel Albarran Obdulia Rabal Antonio Cebri�� Patricia Alfonso Jesus Fominaya Oliver Renner Sandra Peregrina David Soil��n Pl��cido A. Ceballos Ana-Isabel Hern��ndez Milagros Lorenzo Paolo Pevarello Teresa G. Granda Guido Kurz Amancio Carnero James R. Bischoff 《The Journal of biological chemistry》2009,284(41):28392-28400
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David C. Smithson Jeongmi Lee Anang A. Shelat Margaret A. Phillips R. Kiplin Guy 《The Journal of biological chemistry》2010,285(22):16771-16781
Human African trypanosomiasis, caused by the eukaryotic parasite Trypanosoma brucei, is a serious health problem in much of central Africa. The only validated molecular target for treatment of human African trypanosomiasis is ornithine decarboxylase (ODC), which catalyzes the first step in polyamine metabolism. Here, we describe the use of an enzymatic high throughput screen of 316,114 unique molecules to identify potent and selective inhibitors of ODC. This screen identified four novel families of ODC inhibitors, including the first inhibitors selective for the parasitic enzyme. These compounds display unique binding modes, suggesting the presence of allosteric regulatory sites on the enzyme. Docking of a subset of these inhibitors, coupled with mutagenesis, also supports the existence of these allosteric sites. 相似文献
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Kyung Ah Han Hye Seon Kang Jee Won Lee Lang Yoo Eunju Im Ahyoung Hong Yun Ju Lee Woo Hyun Shin Kwang Chul Chung 《PloS one》2014,9(8)
Regulator of calcineurin 1 (RCAN1; also referred as DSCR1 or MCIP1) is located in close proximity to a Down syndrome critical region of human chromosome 21. Although RCAN1 is an endogenous inhibitor of calcineurin signaling that controls lymphocyte activation, apoptosis, heart development, skeletal muscle differentiation, and cardiac function, it is not yet clear whether RCAN1 might be involved in other cellular activities. In this study, we explored the extra-functional roles of RCAN1 by searching for novel RCAN1-binding partners. Using a yeast two-hybrid assay, we found that RCAN1 (RCAN1-1S) interacts with histone deacetylase 3 (HDAC3) in mammalian cells. We also demonstrate that HDAC3 deacetylates RCAN1. In addition, HDAC3 increases RCAN1 protein stability by inhibiting its poly-ubiquitination. Furthermore, HDAC3 promotes RCAN1 nuclear translocation. These data suggest that HDAC3, a new binding regulator of RCAN1, affects the protein stability and intracellular localization of RCAN1. 相似文献