Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines
Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines
复制标题
DOI：
10.1016/j.leukres.2008.10.026
复制
发表时间：
2009-05-01
影响因子：
2.7
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
--
作者：
Guo, Dongmei;Ye, Jingjing;Ji, Chunyan
Notch-1基因功能获得突变在T细胞淋巴母细胞白血病(T-ALL)中很常见，这使得该受体成为伽玛分泌酶抑制剂(GSI)等药物的潜在靶点。然而，GSI似乎只在一小部分具有组成性Notch-1活性的细胞系中活跃，而且Notch信号的下游反应只被部分了解。为了进一步研究增殖抑制和细胞凋亡的分子机制，探索有效的下游靶基因，我们利用RNA干扰(RNAi)技术下调了GSIS耐药T-ALL细胞中Notch-1的表达。结果表明，小干扰RNA(SiRNA)下调Notch-1的表达可通过诱导G(0)/G(1)期细胞周期停滞和细胞凋亡而抑制SUpT1细胞的增殖。Notch-1的下调可能通过调节细胞周期调控蛋白cyClinD1、c1和p21的表达以及Akt信号的活性而起到抑制细胞增殖和诱导细胞凋亡的作用。此外，我们的结果表明，下调Notch-1信号可以使SupT1细胞对阿霉素敏感。综上所述，细胞周期调节蛋白和Akt信号可能是T-ALL的诱人靶点。(C)2008爱思唯尔有限公司。保留所有权利-
Gain-of-function mutations in Notch-1 are common in T-cell lymphoblastic leukemia (T-ALL), making this receptor a promising target lot drugs such as gamma-secretase inhibitors (GSIs). However, GSIs seem to be active in only a small fraction off-ALL cell lines with constitutive Notch-1 activity and the downstream response of Notch signaling is only partially understood. To further investigate the molecular mechanisms underlying proliferation suppression and apoptosis and explore effective downstream target genes, we used RNA interference (RNAi) technology to down-regulate the expression of Notch-1 in GSIs-resistant T-ALL cell lines. Results showed that down-regulation of Notch-1 by transfection of a small interfering RNA (siRNA) Could cause SUpT1 cells proliferation inhibition by inducing G(0)/G(1) cell cycle arrest and apoptosis. The proliferation inhibitory and apoptotic effects resulting from down-regulation of Notch-1 may be mediated through regulating the expression of cell cycle regulatory proteins cyclin D1, C1 and p21 and the activity of Akt signaling. In addition, Our results demonstrated that down-regulation of Notch-1 signaling could sensitize SupT1 cells to adriamycin. Taken together, cell cycle regulatory proteins and Akt signaling may be attractive targets in T-ALL. (C) 2008 Elsevier Ltd. All rights reserved-