Zhong Shuping, Goto Hidemasa, Inagaki Masaki, Dong Zigang
The Hormel Institute, University of Minnesota, 801, 16th Avenue NE, Austin, MN 55912, USA.
Oncogene. 2003 Aug 14;22(34):5291-7. doi: 10.1038/sj.onc.1206507.
Trichostatin A (TSA), a histone deacetylase inhibitor, strongly increases acetylation of the N-terminal tails of histone H3. Many studies have correlated the function of TSA with the hyperacetylation of histone. Although histone H3 is known to be phosphorylated, the effect of acetylation on phosphorylation is not known. Here, we report that in JB6 cells, TSA induces both acetylation at lysine 9 and phosphorylation at serine 28 of histone H3. UVB irradiation, which is known to induce phosphorylation at serine 28, did not significantly affect phosphorylation of histone H3 in TSA-pretreated JB6 cells. In contrast, TSA markedly increased phosphorylation and acetylation of histone H3 in UVB-pretreated JB6 cells. TSA strongly activated MAP kinases. Moreover, PD98059 and SB202190 inhibited TSA-induced phosphorylation but not acetylation of histone H3. Dominant negative mutant ERK2 and dominant negative mutant p38 kinase blocked TSA-stimulated phosphorylation of histone H3 at serine 28. The results indicate that TSA-induced phosphorylation of histone H3 at serine 28 occurs through activation of the MAP kinase pathway and phosphorylated histone H3 is more sensitive to TSA-induced hyperacetylation. The facilitation of phosphorylation and acetylation of histone H3 induced by TSA may play a critical regulatory role in chromatin remodeling and gene expression.
曲古抑菌素A（TSA）是一种组蛋白去乙酰化酶抑制剂，能强烈增加组蛋白H3 N端尾巴的乙酰化。许多研究已将TSA的功能与组蛋白的高乙酰化联系起来。尽管已知组蛋白H3会发生磷酸化，但乙酰化对磷酸化的影响尚不清楚。在此，我们报告在JB6细胞中，TSA可诱导组蛋白H3赖氨酸9位的乙酰化和丝氨酸28位的磷酸化。已知紫外线B（UVB）照射可诱导丝氨酸28位的磷酸化，但在经TSA预处理的JB6细胞中，UVB照射对组蛋白H3的磷酸化没有显著影响。相反，TSA在经UVB预处理的JB6细胞中显著增加了组蛋白H3的磷酸化和乙酰化。TSA强烈激活丝裂原活化蛋白激酶（MAP激酶）。此外，PD98059和SB202190可抑制TSA诱导的组蛋白H3磷酸化，但不抑制其乙酰化。显性负性突变体ERK2和显性负性突变体p38激酶可阻断TSA刺激的组蛋白H3丝氨酸28位的磷酸化。结果表明，TSA诱导的组蛋白H3丝氨酸28位的磷酸化是通过MAP激酶途径的激活发生的，且磷酸化的组蛋白H3对TSA诱导的高乙酰化更敏感。TSA诱导的组蛋白H3磷酸化和乙酰化的促进作用可能在染色质重塑和基因表达中起关键的调节作用。
