Inhibition of histone acetyltransferase by glycosaminoglycans.
Inhibition of histone acetyltransferase by glycosaminoglycans.
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DOI：
10.1002/jcb.21803
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发表时间：
2008-09-01
影响因子：
4
通讯作者：
Nugent, Matthew A.
中科院分区：
文献类型：
--
作者：
Buczek-Thomas, Jo Ann;Hsia, Edward;Rich, Celeste B.;Foster, Judith A.;Nugent, Matthew A.
组蛋白乙酰转移酶（HAT）是一类参与调节染色质结构和基因表达的酶。HAT活性的改变与许多疾病有关，但对HAT的调节知之甚少。在这项研究中，我们报告，糖胺聚糖是p300和pCAF HAT活性的有效抑制剂，在体外，肝素和硫酸乙酰肝素蛋白聚糖是最有效的抑制剂。并探讨了肝素抑制作用的机理。肝素抑制HAT活性的能力部分取决于其大小和结构，因为小的肝素衍生寡糖（> 8个糖）和N-乙酰化或O-乙酰化肝素显示出降低的抑制活性。肝素被证明与pCAF结合;酶试验表明，肝素显示出竞争性抑制剂的特征，导致pCAF对组蛋白H4的表观Km增加约50倍。从角膜和肺成纤维细胞中分离的硫酸乙酰肝素蛋白聚糖抑制HAT活性的效果与肝素相似。作为内源性糖胺聚糖可能参与调节组蛋白乙酰化的证据，直接向肺成纤维细胞中加入肝素导致处理6小时后组蛋白H3乙酰化降低约50%。此外，与野生型亲本细胞相比，缺乏糖胺聚糖合成的中国仓鼠卵巢细胞显示乙酰化组蛋白H3水平增加。糖胺聚糖代表了一类新的HAT抑制剂，其可能通过调节组蛋白乙酰化而参与调节细胞功能。
Histone acetyltransferases (HATs) are a class of enzymes that participate in modulating chromatin structure and gene expression. Altered HAT activity has been implicated in a number of diseases, yet little is known about the regulation of HATs. In this study, we report that glycosaminoglycans are potent inhibitors of p300 and pCAF HAT activities in vitro, with heparin and heparan sulfate proteoglycans being the most potent inhibitors. The mechanism of inhibition by heparin was investigated. The ability of heparin to inhibit HAT activity was in part dependent upon its size and structure, as small heparin-derived oligosaccharides (> 8 sugars) and N-desulfated or O-desulfated heparin showed reduced inhibitory activity. Heparin was shown to bind to pCAF; and enzyme assays indicated that heparin shows the characteristics of a competitive-like inhibitor causing an ~50-fold increase in the apparent Km of pCAF for histone H4. Heparan sulfate proteoglycans isolated from corneal and pulmonary fibroblasts inhibited HAT activity with similar effectiveness as heparin. As evidence that endogenous glycosaminoglycans might be involved in modulating histone acetylation, the direct addition of heparin to pulmonary fibroblasts resulted in an ~50% reduction of histone H3 acetylation after 6 hours of treatment. In addition, Chinese hamster ovary cells deficient in glycosaminoglycan synthesis showed increased levels of acetylated histone H3 compared to wild-type parent cells. Glycosaminoglycans represent a new class of HAT inhibitors that might participate in modulating cell function by regulating histone acetylation.
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影响因子：
1.6
作者：
Brown, CT;Lin, P;Trinkaus-Randall, V
通讯作者：
Trinkaus-Randall, V
影响因子：
5.6
作者：
CASTELLOT, JJ;WONG, K;KARNOVSKY, MJ
通讯作者：
KARNOVSKY, MJ
DOI：
10.1016/0304-4165(86)90306-5
发表时间：
1986-09-04
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
FARNDALE, RW;BUTTLE, DJ;BARRETT, AJ
通讯作者：
BARRETT, AJ
影响因子：
4
作者：
Carreras, I;Rich, CB;Foster, JA
通讯作者：
Foster, JA
影响因子：
5.6
作者：
CASTELLOT, JJ;COCHRAN, DL;KARNOVSKY, MJ
通讯作者：
KARNOVSKY, MJ