哈佛《Nature》Notch信号反其道而行之

　　

生物通报道，哈佛大学生化与生物系，哈佛-MIT联合Broad 研究所，Dana-Farber癌症研究所等处的科学家在最新一期的Nature杂志上发表Notch信号通路研究进展文章Direct inhibition of the NOTCH transcription factor complex。

 

Notch基因最早发现于果蝇，部分功能缺失导致翅缘缺刻。Notch信号通路是进化中高度保守的信号转导通路, 其调控细胞增殖、 分化和凋亡的功能涉及几乎所有组织和器官。Notch是一类穿膜受体，广泛存在于所有已知动物细胞中。Notch介导细胞与细胞间的局部信号传递及相应的信号级联反应。

 

在无脊椎动物和脊椎动物发育过程中,Notch信号对细胞的命运决定起关键作用.通过Notch受体的信号传递能够扩大并固化相邻细胞之间的分子差异,最终决定细胞的命运。

 

同大多数转录因子一样，Notch过去也被认为是不能用可透过细胞的合成分子来定位的。但是现在，哈佛大学的科学家们设计了一个很有希望成为Notch拮抗剂的分子（多肽分子）。

 

功能测试发现，该分子可在小鼠模型中有效抑制白血病的发展。该分子就是由烃类组成的肽SAHM1，可通过阻止活性转录复合物的形成来发挥作用。

 

SAHM1为研究Notch的作用提供一个有潜在价值的工具，同时也为治疗药物提供一个起点。另外，转录激活复合物的直接定位也许还适用于以前被认为不可定位的几个其他转录因子复合物。

（生物通 小茜）

Direct inhibition of the NOTCH transcription factor complex

Raymond E. Moellering1,2,3, Melanie Cornejo4, Tina N. Davis6, Cristina Del Bianco5, Jon C. Aster5, Stephen C. Blacklow5, Andrew L. Kung6, D. Gary Gilliland4,7, Gregory L. Verdine1,3 & James E. Bradner2,3,8

 

Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA

Chemical Biology Program, Broad Institute of Harvard & MIT, Cambridge, Massachusetts 02142, USA

Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

Division of Hematology, Brigham & Women's Hospital,

Department of Pathology, Brigham & Women's Hospital,

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital,

Howard Hughes Medical Institute,

Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Gregory L. Verdine1,3James E. Bradner2,3,8 Correspondence and requests for materials should be addressed to J.E.B. (Email: [e-mail]) or G.L.V. (Email: [e-mail]).

 

【Abstract】

Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized -helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.