Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, 440-746, Republic of Korea.
Cell Signal. 2011 Nov;23(11):1876-84. doi: 10.1016/j.cellsig.2011.07.006. Epub 2011 Jul 14.
Esco2 is an acetyltransferase that is required for the establishment of sister chromatid cohesion. Roberts-SC phocomelia (RBS) syndrome caused by the mutations of Esco2 gene, is an autosomal recessive development disorder characterized by growth retardation, limb reduction and craniofacial abnormalities including cleft lip and palate. Here, we show that Esco2 protein co-immunoprecipitates with Notch but not with CBF1. Esco2 represses the transactivational activity of Notch protein in an acetyltransferase-independent manner. Chromatin immunoprecipitation experiments suggest that Esco2 might regulate the activity of NICD-CBF1 via attenuating NICD binding to CBF1 on the promoter of Hes1, the downstream target gene of Notch. Furthermore, we demonstrate that the overexpression of Esco2 promotes the neuronal differentiation of P19 embryonic carcinoma cells and C17.2 neural progenitor cells and the knockdown of Esco2 by siRNA blocks the differentiation. The inhibitory effects of Notch protein on neuronal differentiation of P19 cells was suppressed by Esco2 overexpression. Taken together, our study suggests that Esco2 may play an important role in neurogenesis by attenuating Notch signaling to promote neuronal differentiation.
ESCO2 是一种乙酰转移酶，对于姐妹染色单体的黏合建立是必需的。ESCO2 基因突变导致的罗伯茨综合征伴短肢畸形（Roberts-SC phocomelia，RBS）综合征是一种常染色体隐性发育障碍，其特征为生长迟缓、肢体缺失以及颅面异常，包括唇腭裂。在这里，我们发现 ESC02 蛋白与 Notch 共免疫沉淀，但不与 CBF1 共沉淀。ESCO2 以一种不依赖乙酰转移酶的方式抑制 Notch 蛋白的转录激活活性。染色质免疫沉淀实验表明，ESCO2 可能通过减弱 NICD 与启动子上的 CBF1 的结合来调节 NICD-CBF1 的活性，而启动子是 Notch 的下游靶基因 Hes1 的所在位置。此外，我们证明过表达 ESC02 可促进 P19 胚胎癌细胞和 C17.2 神经前体细胞的神经元分化，而 siRNA 敲低 ESC02 则阻止分化。Notch 蛋白对 P19 细胞的神经元分化的抑制作用被 ESC02 的过表达所抑制。综上所述，我们的研究表明，ESCO2 可能通过减弱 Notch 信号通路来促进神经元分化，从而在神经发生中发挥重要作用。
