Corre Sébastien, Primot Aline, Baron Yorann, Le Seyec Jacques, Goding Colin, Galibert Marie-Dominique
Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted RH8 OTL, United Kingdom.
J Biol Chem. 2009 Jul 10;284(28):18851-62. doi: 10.1074/jbc.M808605200. Epub 2009 Apr 23.
How transcription factors interpret the output from signal transduction pathways to drive distinct programs of gene expression is a key issue that underpins development and disease. The ubiquitously expressed basic-helix-loop-helix leucine zipper upstream stimulating factor-1 binds E-box regulatory elements (CANNTG) to regulate a wide number of gene networks. In particular, USF-1 is a key component of the tanning process. Following UV irradiation, USF-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the POMC, MC1R, TYR, TYRP-1 and DCT genes. However, how phosphorylation on Thr-153 might affect the activity of USF-1 is unclear. Here we show that, in response to DNA damage, oxidative stress and cellular infection USF-1 is acetylated in a phospho-Thr-153-dependent fashion. Phospho-acetylated USF-1 is nuclear and interacts with DNA but displays altered gene regulatory properties. Phospho-acetylated USF-1 is thus proposed to be associated with loss of transcriptional activation properties toward several target genes implicated in pigmentation process and cell cycle regulation. The identification of this critical stress-dependent USF-1 modification gives new insights into understanding USF-1 gene expression modulation associated with cancer development.
转录因子如何解读信号转导通路的输出以驱动不同的基因表达程序是一个支撑发育和疾病的关键问题。普遍表达的碱性螺旋-环-螺旋亮氨酸拉链上游刺激因子-1（USF-1）结合E-box调控元件（CANNTG）以调节众多基因网络。特别是，USF-1是晒黑过程的关键组成部分。紫外线照射后，USF-1在苏氨酸153位点被p38应激激活激酶磷酸化，并直接上调阿黑皮素原（POMC）、黑素皮质素受体1（MC1R）、酪氨酸酶（TYR）、酪氨酸酶相关蛋白-1（TYRP-1）和二羟基吲哚羧酸（DCT）基因的表达。然而，苏氨酸153位点的磷酸化如何影响USF-1的活性尚不清楚。在此我们表明，在DNA损伤、氧化应激和细胞感染的情况下，USF-1以磷酸化苏氨酸153依赖的方式被乙酰化。磷酸化乙酰化的USF-1定位于细胞核并与DNA相互作用，但显示出改变的基因调控特性。因此，磷酸化乙酰化的USF-1被认为与对参与色素沉着过程和细胞周期调控的几个靶基因的转录激活特性丧失有关。这种关键的应激依赖性USF-1修饰的鉴定为理解与癌症发展相关的USF-1基因表达调控提供了新的见解。
