Peng Y, Stewart D, Li W, Hawkins M, Kulak S, Ballermann B, Jahroudi N
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Oncogene. 2007 Nov 29;26(54):7576-83. doi: 10.1038/sj.onc.1210565. Epub 2007 Jun 18.
Post-irradiation complications including thrombus formation result from increased procoagulant activity of vascular endothelial cells and elevated levels of von Willebrand factor (VWF) contribute to this process. We have previously demonstrated that irradiation induction of the VWF is mediated through interaction of NF-Y transcription factor with its cognate binding site in the VWF promoter. We have also demonstrated that irradiation increases the association of NF-Y with histone acetyltransferase p300/CBP-associated factor (PCAF). We now report that irradiation decreases the association of NF-Y with histone deacetylase 1 (HDAC1). We demonstrate that irradiation-induced changes in association of NF-Y with HDAC1 and PCAF lead to increased PCAF recruitment to the VWF promoter, increased association of acetylated histone H4 with the VWF promoter and subsequently increased transcription. We also demonstrate that this process is correlated to dephosphorylation of HDAC1 and is inhibited by calyculin A, an inhibitor of protein phosphatase1.
包括血栓形成在内的辐射后并发症是由血管内皮细胞促凝活性增加所致，而血管性血友病因子（VWF）水平升高有助于这一过程。我们之前已证明，VWF的辐射诱导是通过NF-Y转录因子与其在VWF启动子中的同源结合位点相互作用介导的。我们还证明，辐射会增加NF-Y与组蛋白乙酰转移酶p300/CBP相关因子（PCAF）的结合。我们现在报告，辐射会降低NF-Y与组蛋白去乙酰化酶1（HDAC1）的结合。我们证明，辐射诱导的NF-Y与HDAC1和PCAF结合的变化导致PCAF向VWF启动子的募集增加、乙酰化组蛋白H4与VWF启动子的结合增加，随后转录增加。我们还证明，这一过程与HDAC1的去磷酸化相关，并受到蛋白磷酸酶1抑制剂冈田酸的抑制。
