Olsson André, Olsson Inge, Dhanda Rakesh Singh
Department of Hematology, BMC, Lund, Sweden.
Biochim Biophys Acta. 2008 Oct;1779(10):590-8. doi: 10.1016/j.bbagrm.2008.06.001. Epub 2008 Jun 10.
The leukaemia-associated eight-twenty-one (ETO) family members ETO, MTG16 (Myeloid Translocation Gene on chromosome 16) and MTGR1 (Myeloid Transforming Gene-Related protein1) are putative transcriptional repressor proteins, which form complexes with coregulatory nuclear corepressors such as SIN3 (SWI-Independent) and N-CoR (Nuclear receptor Co Repressor). In acute myeloid leukaemia (AML), fusion proteins involving the transcription factor AML1 and corepressors ETO or MTG16 are recurrently found. We investigated transcriptional repression by the ETO family members ETO and MTG16 with attention to the conserved Nervy Homology Regions (NHRs) and the interacting corepressors human SIN3B (hSIN3B) and N-CoR. Transcriptional repression was examined in a cell line by a GAL4-thymidine kinase luciferase reporter to which the corepressors were tethered through a binding domain. ETO- and MTG16-mediated repression was found to be independent of deletion of the oligomerization NHR2, but deletion of NHR4 and in particular combined deletion of NHR2 and NHR4 lowered the capacity for repression. An interaction was observed between the corepressors hSIN3B and N-CoR and these two proteins cooperated for transcriptional repression independent of co-transfected ETO and MTG16. Transcriptional repression mediated by ETO and MTG16 was only slightly strengthened by coexpression of hSIN3B or N-CoR and was dependent on HDAC activity. Our data indicate that ETO family member-mediated oligomerization and repression can be distinct events and that interaction between ETO family members and hSIN3B or N-CoR may not necessarily strengthen transcriptional repression.
白血病相关的八 - 二十一（ETO）家族成员ETO、MTG16（16号染色体上的髓系易位基因）和MTGR1（髓系转化基因相关蛋白1）是假定的转录抑制蛋白，它们与诸如SIN3（SWI独立）和N - CoR（核受体共抑制因子）等共调节性核共抑制因子形成复合物。在急性髓系白血病（AML）中，经常发现涉及转录因子AML1和共抑制因子ETO或MTG16的融合蛋白。我们研究了ETO家族成员ETO和MTG16的转录抑制作用，重点关注保守的神经同源区域（NHRs）以及与之相互作用的共抑制因子人SIN3B（hSIN3B）和N - CoR。通过GAL4 - 胸苷激酶荧光素酶报告基因在细胞系中检测转录抑制作用，共抑制因子通过结合结构域与之相连。发现ETO和MTG16介导的抑制作用与寡聚化NHR2的缺失无关，但NHR4的缺失，特别是NHR2和NHR4的联合缺失会降低抑制能力。观察到共抑制因子hSIN3B和N - CoR之间存在相互作用，并且这两种蛋白协同进行转录抑制，与共转染的ETO和MTG16无关。hSIN3B或N - CoR的共表达仅略微增强了ETO和MTG16介导的转录抑制作用，且该抑制作用依赖于组蛋白去乙酰化酶（HDAC）活性。我们的数据表明，ETO家族成员介导的寡聚化和抑制作用可能是不同的事件，并且ETO家族成员与hSIN3B或N - CoR之间的相互作用不一定会增强转录抑制作用。
