Zhao Jing, Zou Yongxin, Liu Haijing, Wang Huali, Zhang Hong, Hou Wei, Li Xin, Jia Xinying, Zhang Jing, Hou Lin, Zhang Bo
Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
Biochim Biophys Acta. 2014 Sep;1843(9):1851-64. doi: 10.1016/j.bbamcr.2014.04.021. Epub 2014 Apr 25.
Centrosome amplification, which is a characteristic of cancer cells, has been understood as a driving force of genetic instability in the development of cancer. In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions. Here we identify TEIF as a downstream effector in EGF/PI3K/Akt signaling. The addition of EGF or transfection of active Akt stimulates centrosome TEIF distribution, resulting in an increase of centrosome splitting and amplification, while inhibitors of either PI3K or Akt attenuate these changes in TEIF and the associated centrosome status. A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification. Moreover, TEIF closely co-localized with C-NAP1 at the proximal ends of centrioles, and centriolar loading of TEIF stimulated by EGF/Akt could displace C-NAP1, resulting in centrosome splitting. These findings reveal linkage of the EGF/PI3K/Akt signaling pathway to regulation of centrosome status which may act as an oncogenic pathway and induce genetic instability in carcinogenesis.
中心体扩增是癌细胞的一个特征，已被视为癌症发展过程中基因不稳定的驱动力。在之前的研究中，我们证明转录元件相互作用因子（TEIF）分布于中心体，并在生理和病理条件下调节中心体状态。在此，我们确定TEIF是表皮生长因子（EGF）/磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（Akt）信号通路的下游效应器。添加EGF或转染活性Akt可刺激中心体TEIF分布，导致中心体分裂和扩增增加，而PI3K或Akt的抑制剂则可减弱TEIF的这些变化以及相关的中心体状态。一个Akt磷酸化的共有基序（RHRVLT）被证明与中心体TEIF定位有关，该基序的第469位苏氨酸在体外和体内均可能被Akt磷酸化。消除TEIF上的这个磷酸化位点会导致中心体分布减少以及中心体分裂或扩增减少。此外，TEIF在中心粒近端与中心体蛋白1（C-NAP1）紧密共定位，由EGF/Akt刺激的TEIF在中心粒上的负载可取代C-NAP1，导致中心体分裂。这些发现揭示了EGF/PI3K/Akt信号通路与中心体状态调节之间的联系，这可能是一条致癌途径，并在致癌过程中诱导基因不稳定。
