King Isabelle N, Kathiriya Irfan S, Murakami Masao, Nakagawa Masayo, Gardner Kelly A, Srivastava Deepak, Nakagawa Osamu
Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9063, USA.
Biochem Biophys Res Commun. 2006 Jun 23;345(1):446-52. doi: 10.1016/j.bbrc.2006.04.097. Epub 2006 Apr 27.
Notch signaling is central to cell differentiation, organ development, and apoptosis. Upon ligand binding, the Notch intracellular domain (NotchIC) translocates to the nucleus to interact with its DNA-binding partner, RBP-Jkappa. The NotchIC-RBP-Jkappa complex activates target genes, such as those encoding the Hrt and Hes families of basic-helix-loop-helix (bHLH) transcriptional repressors. Hrt transcripts are enriched in the developing cardiovascular system, and mice lacking Hrt2 have cardiac malformations. Here we show that Hrt2 and Hes1 interact with RBP-Jkappa to negatively regulate Notch-dependent activation of Hrt and Hes expression. The bHLH domain of Hrt2 was necessary for this interaction, and disrupting the protein complex abrogated the negative autoregulation. The interaction did not interfere with the formation or DNA-binding of the NotchIC-RBP-Jkappa complex, indicating direct inhibition by Hrt and Hes as co-repressors. These findings suggest a novel mechanism for negative feedback on Notch signaling that requires RBP-Jkappa to interact physically with Hrt and Hes.
Notch信号通路在细胞分化、器官发育和细胞凋亡过程中起着核心作用。配体结合后，Notch细胞内结构域（NotchIC）转位至细胞核，与DNA结合伴侣RBP-Jkappa相互作用。NotchIC-RBP-Jkappa复合物激活靶基因，如编码碱性螺旋-环-螺旋（bHLH）转录抑制因子Hrt和Hes家族的那些基因。Hrt转录本在发育中的心血管系统中富集，缺乏Hrt2的小鼠存在心脏畸形。在此我们表明，Hrt2和Hes1与RBP-Jkappa相互作用，对Notch依赖的Hrt和Hes表达激活起负向调节作用。Hrt2的bHLH结构域对于这种相互作用是必需的，破坏该蛋白复合物可消除负向自调节。这种相互作用并不干扰NotchIC-RBP-Jkappa复合物的形成或DNA结合，表明Hrt和Hes作为共抑制因子进行直接抑制。这些发现提示了一种Notch信号通路负反馈的新机制，该机制要求RBP-Jkappa与Hrt和Hes进行物理相互作用。
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