Stra13 expression is associated with growth arrest and represses transcription through histone deacetylase (HDAC)-dependent and HDAC-independent mechanisms
Stra13 expression is associated with growth arrest and represses transcription through histone deacetylase (HDAC)-dependent and HDAC-independent mechanisms
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DOI：
10.1073/pnas.070526297
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发表时间：
2000-04-11
影响因子：
11.1
通讯作者：
Taneja, R
中科院分区：
文献类型：
--
作者：
Sun, H;Taneja, R
Stra 13是一种转录抑制因子，在其基本螺旋-环-螺旋结构域内与果蝇Hairy、分裂增强子和小鼠Hes 1蛋白相关，这些蛋白与辅抑制因子Groucho相互作用。由于Stra 13缺乏与Groucho相互作用的保守WRPW基序，我们研究了Stra 13介导的转录抑制的功能和机制，这些功能和机制具有几个独特的特征。在这里，我们报告Stra 13表达与几种触发剂如维甲酸和阿司他丁A诱导的细胞生长停滞密切相关（TsA;特异性组蛋白脱乙酰酶抑制剂）以及通过血清饥饿，Stra 13的表达在转录上受到抑制，并通过与辅阻遏物组蛋白去乙酰化酶（HDAC 1）。这种相互作用需要含有三个α-螺旋的Stra 13 C-末端结构域，这也是其抑制活性的功能关键。因此，TSA对HDAC活性的抑制消除了Stra 13介导的对其启动子的抑制，导致Stra 13表达的诱导，这与TSA诱导的生长停滞一致。此外，一旦诱导，Stra 13强烈抑制细胞增殖相关基因c-Myc的表达，通过HDAC 1-独立的途径，涉及其与基础转录因子TFIIB的相互作用，我们的研究表明，Stra 13可能发挥关键作用的信号转导途径，导致生长停滞和终末分化的抑制靶基因通过HDAC依赖和HDAC-独立的机制。
Stra13 is a transcriptional repressor related within its basic helix-loop-helix domain with the Drosophila Hairy, Enhancer of Split, and the mouse Hes1 proteins that interact with the corepressor Groucho. Because Stra13 lacks the conserved WRPW motif for interaction with Groucho, we examined the function and mechanism of transcriptional repression mediated by Stra13 that exhibits several distinctive features, Here, we report that Stra13 expression is closely associated with cell growth arrest induced by several triggers such as retinoic acid and trichostatin A (TsA; a specific histone deacetylase inhibitor) as well as by serum starvation, Stra13 expression is transcriptionally repressed and maintained at a low level in cells through a negative autoregulatory mechanism that is brought about by its interaction with the corepressor histone deacetylase (HDAC1). This interaction requires the Stra13 C-terminal domain containing three alpha-helices, which are also functionally critical to its repressive activity. Thus, inhibition of HDAC activity by TSA abrogates Stra13-mediated repression of its promoter, resulting in induction of Stra13 expression that is coincident with TSA-induced growth arrest. Further, once induced, Stra13 strongly represses the expression of the cell proliferation-associated gene c-Myc through an HDAC1-independent pathway that involves its interaction with the basal transcription factor TFIIB, Our studies indicate that Stra13 may play a key role in signaling pathways that lead to growth arrest and terminal differentiation by repression of target genes via HDAC-dependent and HDAC-independent mechanisms.