Schuettengruber Bernd, Doetzlhofer Angelika, Kroboth Karin, Wintersberger Erhard, Seiser Christian
Institute of Medical Biochemistry, Division of Molecular Biology, University of Vienna, Vienna Biocenter, Dr. Bohr-Gasse 9/2, A-1030 Vienna, Austria.
J Biol Chem. 2003 Jan 17;278(3):1784-93. doi: 10.1074/jbc.M204843200. Epub 2002 Oct 30.
Thymidine kinase (TK) is a growth factor-inducible enzyme that is highly expressed in proliferating mammalian cells. Expression of mouse TK mRNA is controlled by transcriptional and posttranscriptional mechanisms including antisense transcription. Here we report the identification of a novel gene that is divergently transcribed from the bidirectional TK promoter. This gene encodes kynurenine formamidase (KF), an enzyme of the tryptophan metabolism. Whereas the TK gene is induced upon interleukin-2-mediated activation of resting T cells, the KF gene becomes simultaneously repressed. The TK promoter is regulated by E2F, SP1, histone acetyltransferases, and deacetylases. The binding site for the growth-regulated transcription factor E2F is beneficial for TK promoter activity but not required for KF expression. In contrast, the SP1 binding site is crucial for transcription in both directions. Inhibition of histone deacetylases by trichostatin A leads to increased histone acetylation at the TK/KF promoter and thereby to selective activation of the TK promoter and simultaneous shut-off of KF expression. Similarly, TK gene activation by interleukin-2 is linked to histone hyperacetylation, whereas KF expression correlates with reduced histone acetylation. The KF gene is the rare example of a mammalian gene whose expression is linked to histone hypoacetylation at its promoter.
胸苷激酶（TK）是一种生长因子诱导型酶，在增殖的哺乳动物细胞中高度表达。小鼠TK mRNA的表达受转录和转录后机制控制，包括反义转录。在此，我们报告鉴定了一个从双向TK启动子反向转录的新基因。该基因编码犬尿氨酸甲酰胺酶（KF），一种色氨酸代谢酶。当白细胞介素-2介导静止T细胞活化时，TK基因被诱导，而KF基因同时被抑制。TK启动子受E2F、SP1、组蛋白乙酰转移酶和脱乙酰酶调控。生长调节转录因子E2F的结合位点对TK启动子活性有益，但对KF表达不是必需的。相反，SP1结合位点对双向转录至关重要。曲古抑菌素A抑制组蛋白脱乙酰酶会导致TK/KF启动子处组蛋白乙酰化增加，从而导致TK启动子的选择性激活和KF表达的同时关闭。同样，白细胞介素-2对TK基因的激活与组蛋白高度乙酰化有关，而KF表达与组蛋白乙酰化减少相关。KF基因是哺乳动物中罕见的例子，其表达与其启动子处的组蛋白低乙酰化有关。
