Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription
Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription
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DOI：
10.1074/jbc.m409024200
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发表时间：
2004-12-03
影响因子：
4.8
通讯作者：
Kundu, TK
中科院分区：
文献类型：
--
作者：
Balasubramanyam, K;Varier, RA;Kundu, TK
组蛋白和非组蛋白的乙酰化是一种重要的翻译后修饰，参与真核生物以及所有整合到人类基因组中的病毒DNA（例如人类免疫缺陷病毒）的基因表达调控。组蛋白乙酰转移酶（HATs）功能失调通常与多种疾病的表现相关。在这方面，HATs是设计治疗药物的新潜在靶点。在本研究中，我们报道姜黄素（二阿魏酰甲烷），一种香料姜黄中的主要姜黄素类化合物，在体外和体内是p300/CREB结合蛋白（CBP）HAT活性的特异性抑制剂，但不是p300/CBP相关因子的抑制剂。此外，姜黄素在体内还能抑制p300介导的p53乙酰化。它特异性地抑制来自染色质的p300/CBP HAT活性依赖的转录激活，但不抑制来自DNA模板的转录激活。重要的是，姜黄素在体外能抑制p300对HIV - Tat蛋白的乙酰化以及病毒的增殖，这从姜黄素处理SupT1细胞时合胞体形成的抑制中可以看出。因此，靶向p300/CBP的无毒姜黄素可作为组合式艾滋病治疗药物中的先导化合物。
Acetylation of histones and non-histone proteins is an important post-translational modification involved in the regulation of gene expression in eukaryotes and all viral DNA that integrates into the human genome ( e. g. the human immunodeficiency virus). Dysfunction of histone acetyltransferases (HATs) is often associated with the manifestation of several diseases. In this respect, HATs are the new potential targets for the design of therapeutics. In this study, we report that curcumin (diferuloylmethane), a major curcumanoid in the spice turmeric, is a specific inhibitor of the p300/CREB-binding protein (CBP) HAT activity but not of p300/CBP-associated factor, in vitro and in vivo. Furthermore, curcumin could also inhibit the p300-mediated acetylation of p53 in vivo. It specifically represses the p300/CBP HAT activity-dependent transcriptional activation from chromatin but not a DNA template. It is significant that curcumin could inhibit the acetylation of HIV-Tat protein in vitro by p300 as well as proliferation of the virus, as revealed by the repression in syncytia formation upon curcumin treatment in SupT1 cells. Thus, nontoxic curcumin, which targets p300/CBP, may serve as a lead compound in combinatorial HIV therapeutics.