Kim Hee-Sun, Park Jin-Sun, Hong Seok-Jong, Woo Moon-Sook, Kim So-Young, Kim Kwang-Soo
Department of Neuroscience, Ewha Institute of Neuroscience, College of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2003 Dec 26;312(4):950-7. doi: 10.1016/j.bbrc.2003.11.012.
Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to 3,4-dihydroxy-L-phenylalanine, which is the first and rate-limiting step in catecholamine biosynthesis. In the present study, we report that treatment with the histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) or sodium butyrate, prominently induces the TH promoter activity in both non-neuronal and neuronal cell lines. By analyzing a series of deletional reporter constructs, we also determined that the proximal 151bp region of the TH promoter is largely responsible for TSA-mediated activation. Finally, we found that mutation of the Sp1 or CRE site, residing in the proximal area, abolishes TSA-mediated activation, strongly suggesting that the Sp1 and CRE sites may mediate TH promoter activation by inhibition of HDAC. In summary, our results provide a novel regulatory frame in which modulation of chromatin structure by histone deacetylase may contribute to transcriptional regulation of the TH via the Sp1 and/or CRE site.
酪氨酸羟化酶（TH）催化L-酪氨酸转化为3,4-二羟基-L-苯丙氨酸，这是儿茶酚胺生物合成的第一步且是限速步骤。在本研究中，我们报告称，用组蛋白脱乙酰酶（HDAC）抑制剂曲古抑菌素A（TSA）或丁酸钠处理，可显著诱导非神经元和神经元细胞系中的TH启动子活性。通过分析一系列缺失报告构建体，我们还确定TH启动子的近端151bp区域在很大程度上负责TSA介导的激活。最后，我们发现位于近端区域的Sp1或CRE位点发生突变会消除TSA介导的激活，这强烈表明Sp1和CRE位点可能通过抑制HDAC介导TH启动子激活。总之，我们的结果提供了一种新的调节框架，其中组蛋白脱乙酰酶对染色质结构的调节可能通过Sp1和/或CRE位点促进TH的转录调节。
