Ichijo Takamasa, Chrousos George P, Kino Tomoshige
Section on Pediatric Endocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA.
Mol Cell Endocrinol. 2008 Feb 13;283(1-2):19-31. doi: 10.1016/j.mce.2007.10.014. Epub 2007 Nov 17.
Set/template-activating factor (TAF)-Ibeta, part of the Set-Can oncogene product found in acute undifferentiated leukemia, is a component of the inhibitor of acetyltransferases (INHAT) complex. Set/TAF-Ibeta interacted with the DNA-binding domain of the glucocorticoid receptor (GR) in yeast two-hybrid screening, and repressed GR-induced transcriptional activity of a chromatin-integrated glucocorticoid-responsive and a natural promoter. Set/TAF-Ibeta was co-precipitated with glucocorticoid response elements (GREs) of these promoters in the absence of dexamethasone, while addition of the hormone caused dissociation of Set/TAF-Ibeta from and attraction of the p160-type coactivator GRIP1 to the promoter GREs. Set-Can fusion protein, on the other hand, did not interact with GR, was constitutively co-precipitated with GREs and suppressed GRIP1-induced enhancement of GR transcriptional activity and histone acetylation. Thus, Set/TAF-Ibeta acts as a ligand-activated GR-responsive transcriptional repressor, while Set-Can does not retain physiologic responsiveness to ligand-bound GR, possibly contributing to the poor responsiveness of Set-Can-harboring leukemic cells to glucocorticoids.
集落刺激因子/模板激活因子（TAF）-Iβ是急性未分化白血病中发现的Set-Can癌基因产物的一部分，是乙酰转移酶抑制剂（INHAT）复合物的一个组成部分。在酵母双杂交筛选中，Set/TAF-Iβ与糖皮质激素受体（GR）的DNA结合结构域相互作用，并抑制GR诱导的染色质整合糖皮质激素反应元件和天然启动子的转录活性。在没有地塞米松的情况下，Set/TAF-Iβ与这些启动子的糖皮质激素反应元件（GREs）共沉淀，而添加激素会导致Set/TAF-Iβ从启动子GREs上解离，并使p160型共激活因子GRIP1与启动子GREs结合。另一方面，Set-Can融合蛋白不与GR相互作用，与GREs组成性共沉淀，并抑制GRIP1诱导的GR转录活性增强和组蛋白乙酰化。因此，Set/TAF-Iβ作为一种配体激活的GR反应性转录抑制因子，而Set-Can对配体结合的GR不保留生理反应性，这可能导致携带Set-Can的白血病细胞对糖皮质激素反应性差。
