Identification of XAF1 as a novel cell cycle regulator through modulating G(2)/M checkpoint and interaction with checkpoint kinase 1 in gastrointestinal cancer.
Identification of XAF1 as a novel cell cycle regulator through modulating G(2)/M checkpoint and interaction with checkpoint kinase 1 in gastrointestinal cancer.
复制标题
通过调节 G(2)/M 检查点以及与胃肠癌检查点激酶 1 的相互作用，鉴定 XAF1 作为一种新型细胞周期调节剂。
DOI：
10.1093/carcin/bgp155
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发表时间：
2009
期刊：
影响因子：
4.7
通讯作者：
B. Wong
中科院分区：
文献类型：
--
作者：
Jide Wang;Q. Gu;Ming Li;Wenjing Zhang;Mo Yang;B. Zou;Shing Chan;L. Qiao;B. Jiang;Shuiping Tu;Juan Ma;I. Hung;H. Lan;B. Wong
背景与目的
X连锁凋亡相关因子抑制因子1（X-linked inhibitor of apoptosis associated factor 1，XAF 1）是最早发现的一种抑制caspase 3活性的X连锁凋亡抑制因子拮抗剂。它在癌细胞中的表达低于正常组织。XAF 1的过表达可以抑制癌细胞的生长，并使肿瘤坏死因子相关的凋亡诱导配体或依托泊苷诱导的凋亡敏感。本研究旨在阐明XAF 1调控细胞生长的机制。
方法
产生表达XAF 1和载体对照的胃肠（GI）癌细胞系AGS和SW 1116的稳定转染子。检测细胞生长、凋亡、有丝分裂状态和细胞周期分布。用免疫印迹、激酶试验和免疫共沉淀试验研究XAF 1与G（2）/M检查点蛋白的相互作用。有丝分裂灾难的发生，确定异常核和中心体扩增。
结果
我们的研究结果表明，XAF 1过表达抑制血清依赖性癌细胞生长，诱导有丝分裂灾难和G（2）/M细胞周期阻滞。有趣的是，XAF 1主要表达于细胞周期同步化后的G（2）/M期。XAF 1与Chk 1相互作用，激活Chk 1，失活Cdc 25 C，导致Cdc 2-cyclin B复合物失活。抑制Chk 1可解除XAF 1诱导的G（2）/M期阻滞。
结论
我们的研究结果表明XAF 1是一种新的细胞周期调节剂，在G（2）/M期募集，从而揭示了XAF 1的一个新的功能途径，提示XAF 1作为治疗GI癌症的靶点的潜在作用。
BACKGROUND AND AIMS
X-linked inhibitor of apoptosis-associated factor 1 (XAF1) was first recognized as an antagonist of X-linked inhibitor of apoptosis in suppressing caspase 3 activity. It has lower expression in cancer cells than normal tissue. Overexpression of XAF1 can inhibit cancer cell growth and sensitize tumor necrosis factor-related apoptosis-inducing ligand- or etoposide-induced apoptosis. The aim of this study is to elucidate the mechanism of XAF1 in regulating cell growth.
METHODS
Stable transfectants of gastrointestinal (GI) cancer cell lines AGS and SW1116 expressing XAF1 and vector control were generated. Cell growth, apoptosis, mitotic status and cell cycle distribution were assessed. The interaction between XAF1 and G(2)/M checkpoint proteins was evaluated by immunoblotting, kinase assay and co-immunoprecipitation assay. Mitotic catastrophe was identified by occurrence of aberrant nuclei and centrosomal amplification.
RESULTS
Our results showed that overexpression of XAF1 suppressed serum-dependent cancer cell growth, induced mitotic catastrophe and G(2)/M cell cycle arrest. Interestingly, XAF1 was predominantly expressed in G(2)/M phase after cell cycle synchronization. XAF1 interacted with and activated checkpoint kinase 1 (Chk1), inactivated Cdc25C and lead to inactivation of Cdc2-cyclin B complex. Suppression of Chk1 abrogated XAF1-induced G(2)/M arrest.
CONCLUSIONS
Our findings implicate XAF1 as a novel cell cycle modulator that is recruited in G(2)/M phase and thus unravel a novel function pathway of XAF1, suggesting the potential role of XAF1 as the target for the management of GI cancers.
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影响因子：
11.2
作者：
K. Yamane;J. Schupp;T. Kinsella
通讯作者：
K. Yamane;J. Schupp;T. Kinsella
DOI：
10.1073/pnas.0409130102
发表时间：
2005-01-25
影响因子：
11.1
作者：
Huang, XX;Tran, T;Zhang, PM
通讯作者：
Zhang, PM
影响因子：
56.9
作者：
Peng, CY;Graves, PR;PiwnicaWorms, H
通讯作者：
PiwnicaWorms, H
影响因子：
56.9
作者：
Sanchez, Y;Wong, C;Elledge, SJ
通讯作者：
Elledge, SJ