Department of Pediatrics, Division of Pediatric Hematology/Oncology, Vanderbilt Univesity School of Medicine, 397 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232-6310, USA.
Mol Cell Biol. 2010 Apr;30(7):1852-63. doi: 10.1128/MCB.01342-09. Epub 2010 Feb 1.
The Notch signaling pathway regulates gene expression programs to influence the specification of cell fate in diverse tissues. In response to ligand binding, the intracellular domain of the Notch receptor is cleaved by the gamma-secretase complex and then translocates to the nucleus. There, it binds the transcriptional repressor CSL, triggering its conversion to an activator of Notch target gene expression. The events that control this conversion are poorly understood. We show that the transcriptional corepressor, MTG16, interacts with both CSL and the intracellular domains of Notch receptors, suggesting a pivotal role in regulation of the Notch transcription complex. The Notch1 intracellular domain disrupts the MTG16-CSL interaction. Ex vivo fate specification in response to Notch signal activation is impaired in Mtg16-/- hematopoietic progenitors, and restored by MTG16 expression. An MTG16 derivative lacking the binding site for the intracellular domain of Notch1 fails to restore Notch-dependent cell fate. These data suggest that MTG16 interfaces with critical components of the Notch transcription complex to affect Notch-dependent lineage allocation in hematopoiesis.
Notch 信号通路通过调节基因表达程序来影响不同组织中细胞命运的特化。在配体结合后，Notch 受体的细胞内域被 γ-分泌酶复合物切割，然后易位到细胞核。在细胞核内，它与转录抑制因子 CSL 结合，触发其转化为 Notch 靶基因表达的激活剂。控制这种转化的事件还不太清楚。我们发现，转录共抑制因子 MTG16 与 CSL 和 Notch 受体的细胞内域相互作用，表明其在 Notch 转录复合物的调节中起着关键作用。Notch1 细胞内域破坏了 MTG16-CSL 相互作用。在 Mtg16-/-造血祖细胞中，对外源性 Notch 信号激活的命运特化反应受损，而 MTG16 的表达则可以恢复。一种缺乏 Notch1 细胞内域结合位点的 MTG16 衍生物不能恢复 Notch 依赖性细胞命运。这些数据表明，MTG16 与 Notch 转录复合物的关键成分相互作用，影响造血中 Notch 依赖性谱系分配。
