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首页> 外文期刊>Journal of cellular biochemistry. >High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation.
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High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation.

机译：高水平的细胞内多胺促进组蛋白乙酰转移酶活性，导致染色质过度乙酰化。

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摘要

Polyamines stimulate expression of a variety of genes, including many implicated in cell proliferation. Indeed, aberrant expression of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, plays a causal role in tumorigenesis. Gene activity is influenced by dynamic changes in acetylation of nucleosomal histones. Although polyamines influence the histone acetyltransferase and deacetylase activities in cell-free systems, their ability to modulate these enzymes in live cells has never been established. To examine the effects of elevated intracellular levels of ODC and polyamines on gene transcription and histone acetylation, cells were infected with a retrovirus containing a cDNA for ODC. ODC overexpression potentiated the stimulatory effects of histone deacetylase inhibitors on reporter gene expression beyond that promoted by ODC or inhibitor treatment alone. Indeed, elevated intracellular levels of ODC promoted hyperacetylation of histones in several epidermal and fibroblast cell types. The ODC-mediated increase in acetylated histones was abrogated when cells were treated with alpha-difluoromethylornithine, a specific inhibitor of ODC activity, implying a distinct role for polyamines. Specifically, polyamines were found to enhance the action of histone acetyltransferases either directly or indirectly. Our studies document effects of elevated intracellular polyamine levels on histone acetylation in proliferating cells, suggesting a mechanism by which altered polyamine biosynthesis contributes to aberrant expression of genes, facilitating tumor growth. In addition, these studies may have implications for the development of drugs designed to regulate enzymes that modify the acetylation status of histones. Copyright 2000 Wiley-Liss, Inc.
机译：多胺刺激多种基因的表达，包括许多与细胞增殖有关的基因。确实，鸟氨酸脱羧酶（ODC）的异常表达是多胺生物合成中的限速酶，在肿瘤发生中起因果作用。基因活性受核小体组蛋白乙酰化的动态变化影响。尽管多胺会影响无细胞系统中的组蛋白乙酰转移酶和脱乙酰酶活性，但从未确定其调节活细胞中这些酶的能力。为了检查细胞内ODC和多胺水平升高对基因转录和组蛋白乙酰化的影响，用含有ODC cDNA的逆转录病毒感染细胞。 ODC的过表达增强了组蛋白脱乙酰基酶抑制剂对报告基因的刺激作用，超出了单独使用ODC或抑制剂处理所促进的作用。实际上，升高的细胞内ODC水平在几种表皮和成纤维细胞类型中促进了组蛋白的高度乙酰化。当用α-二氟甲基鸟氨酸（一种ODC活性的特异性抑制剂）处理细胞时，ODC介导的乙酰化组蛋白的增加被消除了，这暗示了多胺的独特作用。具体而言，发现多胺直接或间接增强组蛋白乙酰转移酶的作用。我们的研究记录了细胞内多胺水平升高对增殖细胞中组蛋白乙酰化的影响，表明改变多胺生物合成机制可导致基因异常表达，从而促进肿瘤生长。此外，这些研究可能对开发旨在调节可修饰组蛋白乙酰化状态的酶的药物产生影响。版权所有2000 Wiley-Liss，Inc.

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