The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction
The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction
复制标题
DOI：
10.1074/jbc.m410578200
复制
发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Nagai, R
中科院分区：
文献类型：
--
作者：
Matsumura, T;Suzuki, T;Nagai, R
转录受转录因子和相关辅因子的网络调节，这些辅因子与一般转录机制协同作用。阐明它们的潜在相互作用对于理解调节转录的机制是重要的。最近，我们已经表明，Kruppel样因子KLF 5，锌指因子的Sp/KLF家族的成员和心血管重构的关键调节剂，正调节乙酰化酶p300和负调节致癌调节SET通过耦合相互作用和调节乙酰化。在这里，我们已经表明，去乙酰化酶HDAC 1可以通过直接相互作用负调控KLF 5。KLF 5在细胞内和体外与HDAC 1相互作用。凝胶位移DNA结合实验表明，它们的相互作用抑制KLF 5的DNA结合活性，表明HDAC 1的性质直接影响转录因子的DNA结合亲和力。报告基因测定还显示HDAC 1抑制KLF 5依赖性启动子激活。此外，HDAC 1的过表达抑制KLF 5依赖的激活其内源性下游基因，血小板衍生生长因子-A链基因，当激活佛波醇酯。此外，HDAC 1与KLF 5的第一锌指结合，这是p300与KLF 5相互作用的同一区域，有趣的是，HDAC 1抑制p300与KLF 5的结合。乙酰化酶和脱乙酰化酶之间的直接竞争相互作用迄今为止是未知的。总的来说，转录因子KLF 5通过直接影响其活性（DNA结合活性，启动子激活）并进一步通过抑制与p300的相互作用而受到脱乙酰酶HDAC 1的负调控。这些发现提示了去乙酰化酶在转录调控中的新作用和机制。
Transcription is regulated by a network of transcription factors and related cofactors that act in concert with the general transcription machinery. Elucidating their underlying interactions is important for understanding the mechanisms regulating transcription. Recently, we have shown that Kruppel-like factor KLF5, a member of the Sp/KLF family of zinc finger factors and a key regulator of cardiovascular remodeling, is regulated positively by the acetylase p300 and negatively by the oncogenic regulator SET through coupled interaction and regulation of acetylation. Here, we have shown that the deacetylase HDAC1 can negatively regulate KLF5 through direct interaction. KLF5 interacts with HDAC1 in the cell and in vitro. Gel shift DNA binding assay showed that their interaction inhibits the DNA binding activity of KLF5, suggesting a property of HDAC1 to directly affect the DNA binding affinity of a transcription factor. Reporter assay also revealed that HDAC1 suppresses KLF5-dependent promoter activation. Additionally, overexpression of HDAC1 suppressed KLF5-dependent activation of its endogenous downstream gene, platelet-derived growth factor-A chain gene, when activated by phorbol ester. Further, HDAC1 binds to the first zinc finger of KLF5, which is the same region where p300 interacts with KLF5 and, intriguingly, HDAC1 inhibits binding of p300 to KLF5. Direct competitive interaction between acetylase and deacetylase has been hitherto unknown. Collectively, the transcription factor KLF5 is negatively regulated by the deacetylase HDAC1 through direct effects on its activities (DNA binding activity, promoter activation) and further through inhibition of interaction with p300. These findings suggest a novel role and mechanism for regulation of transcription by deacetylase.