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JBC:发现可调控细胞周期的新蛋白

来源:微生物研究所 2009-03-30 16:55

近日,中科院微生物所百人计划引进人才叶昕研究员课题组通过研究,发现了与细胞周期调控的关键调控分子Cyclins/Cdks新相互作用蛋白-锚蛋白Ankrd17,研究结果发表在Journal of  Biological Chemistry  284期第12卷上。

细胞周期在细胞的生长,分化及分裂过程中扮演着极其重要的角色,细胞周期的失控伴随着肿瘤的发生或细胞的凋亡。Cyclins/Cdks蛋白激酶为细胞周期调控最为关键的调控分子,其中CyclinE/Cdk2在细胞周期的G1/S检验点转换过程中发挥着极其关键的作用。目前已经发现了一些与CyclinE/Cdk2相互作用的蛋白参与细胞周期的调控,但是CyclinE/Cdk2调控细胞周期的详尽的信号转导网络尚未明晰。

为了进一步阐明CyclinE/Cdk2在细胞周期G1/S检验点的功能,我所叶昕研究员课题组的博士研究生邓敏和李发慧,通过TAP亲和纯化技术筛选到CyclinE/Cdk2新相互作用蛋白-锚蛋白Ankrd17,并对Ankrd17调控细胞周期的机理进行系统的研究,这在国际上尚属首次。该研究通过体外激酶反应及质谱分析等手段,证实Ankrd17为Cyclin  E/Cdk2的底物,并定位其磷酸化位点;  通过免疫荧光染色、RNAi干扰及流式细胞术等方法发现Ankrd17能促进细胞周期的进行,  同时发现Ankrd17通过调控DNA复制相关蛋白Cdc6和PCNA与DNA的结合而参与DNA复制;  研究结果表明Ankrd17是细胞周期G1/S期转换过程中的一种正调控蛋白。

该项研究结果有助于进一步理解CyclinE/Cdk2激酶复合体在细胞周期调控及肿瘤发生过程中的作用,进而为寻找新的抗肿瘤治疗靶标提供理论依据。(生物谷Bioon.com)

生物谷推荐原始出处:

J. Biol. Chem., Vol. 284, Issue 12, 7875-7888, March 20, 2009

Min Deng1, Fahui Li1, Bryan A. Ballif?2, Shan Li||, Xi Chen**, Lin Guo**, and Xin Ye3

From the  Department of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China, the ?Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, the ||Shandong Normal University, Jinan, Shandong 250014, China, the **College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China, and the Graduate University of Chinese Academy of Sciences, Beijing 100101, China

Cyclin E/Cdk2 is a key regulator in G1-S transition. We have identified a novel cyclin E/Cdk2 substrate called Ankrd17 (ankyrin repeat protein 17) using the TAP tag purification technique. Ankrd17 protein contains two clusters of a total 25 ankyrin repeats at its N terminus, one NES (nuclear exporting signal) and one NLS (nuclear localization signal) in the middle, and one RXL motif at its C terminus. Ankrd17 is expressed in various tissues and associates with cyclin E/Cdk2 in an RXL-dependent manner. It can be phosphorylated by cyclin E/Cdk2 at 3 phosphorylation sites (Ser1791, Ser1794, and Ser2150). Overexpression of Ankrd17 promotes S phase entry, whereas depletion of Ankrd17 expression by small interfering RNA inhibits DNA replication and blocks cell cycle progression as well as up-regulates the expression of p53 and p21. Ankrd17 is localized to the nucleus and interacts with DNA replication factors including MCM family members, Cdc6 and PCNA. Depletion of Ankrd17 results in decreased loading of Cdc6 and PCNA onto DNA suggesting that Ankrd17 may be directly involved in the DNA replication process. Taken together, these data indicate that Ankrd17 is an important downstream effector of cyclin E/Cdk2 and positively regulates G1/S transition.

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