Research on Gene Expression Network via histone acetylation

SKI基因最初被确认为致癌基因。我们已经证明，c-ski原癌基因产物(c-ski)直接与共抑制因子N-COR和mSin3A结合，并与组蛋白脱乙酰酶(HDAC)形成复合体。C-Ski是一种共抑制因子，在肿瘤抑制因子Mad和Rb以及核激素受体介导的转录抑制中是必需的。我们已经产生了缺乏sno(滑雪相关新基因)基因的突变小鼠，sno基因编码与ski相关的基因。SNO对早期发育的囊胚形成是必不可少的，而缺乏SNO的胚胎在发育的早期阶段就会死亡。SNO杂合子突变体看起来是健康的，但在他们身上观察到了自发的肿瘤。此外，当它们被化学致癌物DMBA处理时，它们对肿瘤发生的敏感性增加，在SKI杂合突变小鼠中也获得了类似的结果。这些结果表明，SKI和sNO基因既可以作为癌基因，也可以作为肿瘤抑制基因，这取决于细胞环境。我们还产生了缺乏CBP的突变小鼠，CBP是最著名的包含组蛋白乙酰化酶活性的辅助激活剂。CBP缺陷的胚胎在E12.5-E14.5死于脑出血。出血是由于血管形成受损所致，提示CBP在血管形成中的重要作用。CBP基因缺陷的胚胎在胎肝中也表现出部分造血功能受损。我们发现CBP直接乙酰化c-Myb，而c-Myb的乙酰化增强了c-Myb和CBP之间的结合，这是一个有趣的新机制，共激活剂CBP通过它来调节转录因子的活性。

The ski gene was originally identified as an oncogene. We have demonstrated that c-ski proto-oncogene product (c-Ski) directly associates with co-repressors N-CoR and mSin3A and forms a complex with histone deacetylase (HDAC). c-Ski acts as a co-repressor, and is required for transcriptional repression mediated by tumor suppressors, Mad and Rb, and nuclear hormone receptors . We have generated the mutant mice lacking the sno (ski-related novel) gene, which encodes the ski-related gene. Sno is essential for blastocyst formation in early development, and the sno-deficient embryos die at an early stage of development. The sno heterozygous mutants appeared to be healthy, but spontaneously arisen tumors were observed in them. Furthermore, they have the increased susceptibility to tumorigenesis when they were treated with the chemical carcinogen DMBA.Similar results were also obtained with the ski heterozygous mutant mice. These results indicate that ski and sno genes act as either oncogene or tumor suppressor depending on the cellular context. We also generated the mutant mice lacking CBP, which is the most famous co-activator containing the histone acetylase activity. The Cbp-deficient embryos died at E12.5-E14.5 due to hemorrhage in the brain. Hemorrhage was caused by impaired formation of blood vessel, indicating the important role of CBP for blood vessel formation. The Cbp-deficient embryos also exhibited the partially impaired hematopoesis in fetal liver. We have found that CBP directly acetylates c-Myb, and acetylation of c-Myb enhances the association between c-Myb and CBP.This is an interesting novel mechanism by which co-activator CBP regulates the activity of transcription factor.