Localization of TEIF in the centrosome and its functional association with centrosome amplification in DNA damage, telomere dysfunction and human cancers
Localization of TEIF in the centrosome and its functional association with centrosome amplification in DNA damage, telomere dysfunction and human cancers
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TEIF 在中心体中的定位及其与 DNA 损伤、端粒功能障碍和人类癌症中中心体扩增的功能关联
DOI：
10.1038/onc.2008.503
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发表时间：
2009-03-01
期刊：
影响因子：
8
通讯作者：
Zhang, B.
中科院分区：
文献类型：
--
作者：
Gong, Y.;Sun, Y.;Zhang, B.
中心体扩增和端粒缩短，这是在人类癌症中普遍检测到的，已经涉及到诱导染色体不稳定的肿瘤发生。这两种结构的功能与DNA损伤修复机制密切相关，一些参与端粒维持的因素也参与中心体状态的调节，表明它们在功能上存在联系。我们报道了端粒酶转录元件相互作用因子（TEIF）是人类端粒酶逆转录酶亚基（hTERT）基因的一种反激活因子，在整个细胞周期中分布在中心体中，但在某些条件下其向中心体的转运增加，并且其分布依赖于其c端结构域。通过过表达、多肽表达或缺失TEIF表达的实验调节影响着中心体状态并增加细胞有丝分裂的异常。基因毒性药物和实验性端粒功能障碍也刺激了TEIF在中心体上的定位，并伴有中心体扩增。此外，我们发现TEIF在软组织肉瘤中的表达水平不仅与中心体扩增密切相关，而且与肿瘤的组织学分级也有显著关系。我们的数据证实了TEIF作为中心体调节剂的功能。它参与DNA损伤反应，包括端粒功能障碍和肿瘤发生，表明TEIF可能是癌症发展中中心体扩增和端粒功能障碍联系的一个因素。
Centrosome amplification and telomere shortening, which are commonly detected in human cancers, have been implicated in the induction of chromosome instability in tumorigenesis. The functions of these two structures are closely related to DNA damage repair machinery, and some factors that operate in the maintenance of telomeres also take part in the regulation of centrosome status, suggesting they are functionally linked. We report that TEIF (telomerase transcriptional elements-interacting factor), a transactivator of the hTERT (human telomerase reverse transcriptase subunit) gene, is distributed in the centrosome throughout the cell cycle, but its transport into the centrosome is increased under some conditions, and its distribution is dependent on its C-terminal domain. Experimental modulation of TEIF expression through overexpression, polypeptide expression or depletion affected centrosome status and increased abnormalities of cell mitosis. Localization of TEIF to the centrosome was also stimulated by treatment with genotoxic agents and experimental telomere dysfunction, accompanying centrosome amplification. Moreover, we demonstrated that the expression level of TEIF is not only closely correlated with centrosome amplification in soft tissue sarcomas but it is also significantly related to tumor histologic grade. Our data confirmed TEIF functions as a centrosome regulator. Its participation in DNA damage response, including telomere dysfunction and tumorigenesis, indicates TEIF is likely to be a factor involved in linking centrosome amplification and telomere dysfunction in cancer development.