Acetylation of cAMP-responsive element-binding protein (CREB) by CREB-binding protein enhances CREB-dependent transcription
Acetylation of cAMP-responsive element-binding protein (CREB) by CREB-binding protein enhances CREB-dependent transcription
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DOI：
10.1074/jbc.m300546200
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发表时间：
2003-05-02
影响因子：
4.8
通讯作者：
Kwok, RPS
中科院分区：
文献类型：
--
作者：
Lu, Q;Hutchins, AE;Kwok, RPS
cAMP 反应元件结合蛋白 (CREB) 结合蛋白 (CBP) 的共激活子功能部分是由其组蛋白乙酰转移酶活性引起的。然而，越来越清楚的是，CBP 乙酰化组蛋白和非组蛋白，其中许多是转录因子。在这里，我们研究 CBP 乙酰化酶活性在 CREB 介导的基因表达中的作用。我们发现 CREB 在细胞内被乙酰化，并且在体外，CREB 被 CBP 乙酰化，但不被另一种乙酰酶 p300/CBP 相关因子乙酰化。内的乙酰化位点。 CREB 被映射到 CREB 激活域内的三个赖氨酸。尽管抑制组蛋白脱乙酰酶活性会导致 CREB 或 CBP 介导的基因表达增加，但 CREB 激活域中所有三个假定的乙酰化位点的突变均显着增强了 CREB 激活 cAMP 响应元件依赖性报告基因的能力。此外，这些 CREB 赖氨酸突变不会增加与 CRE 或 CBP 的相互作用。这些数据表明 CREB 的反式激活潜力可能通过 CBP 的乙酰化来调节。我们认为，除了作为桥接分子和组蛋白乙酰转移酶的功能外，CBP 乙酰化 CREB 的能力可能在调节 CREB 介导的基因表达中发挥关键作用。
The coactivator function of cAMP-responsive element-binding protein (CREB)-binding protein (CBP) is partly caused by its histone acetyltransferase activity. However, it has become increasingly clear that CBP acetylates both histones and non-histone proteins, many of which are transcription factors. Here we investigate the role of CBP acetylase activity in CREB-mediated gene expression. We show that CREB is acetylated within the cell and that in vitro, CREB is acetylated by CBP, but not by another acetylase, p300/CBP-associated factor. The acetylation sites within. CREB were mapped to three lysines within the CREB activation domain. Although inhibition of histone deacetylase activity results in an increase of CREB- or CBP-mediated gene expression, mutation of all three putative acetylation sites in the CREB activation domain markedly enhances the ability of CREB to activate a cAMP-responsive element-dependent reporter gene. Furthermore, these CREB lysine mutations do not increase interaction with the CRE or CBP. These data suggest that the transactivation potential of CREB may be modulated through acetylation by CBP. We propose that in addition to its functions as a bridging molecule and histone acetyltransferase, the ability of CBP to acetylate CREB may play a key role in modulating CREB-mediated gene expression.