Entry into mitosis is driven by signaling cascades of mitotic kinases.Our recent studies show that TTK,a kinetochore-associated protein kinase,interacts with CENP-E,a mitotic kinesin located to corona fiber ofkinetoch...Entry into mitosis is driven by signaling cascades of mitotic kinases.Our recent studies show that TTK,a kinetochore-associated protein kinase,interacts with CENP-E,a mitotic kinesin located to corona fiber ofkinetochore.Using immunoelectron microscopy,here we show that TTK is present at the nuclear pore adjacent complex of interphase HeLa cells.Upon nuclear envelope fragmentation,TTK targets to the outermostregion of the developing kinetochores ofmonoorient chromosome as well as to spindle poles.After stable attachment,throughout chromosome congression,TTK is a constituent of the corona fibers,extending up to 90 nm away from the kinetochore outer plate.Upon metaphase alignment,TTK departs from the kinetochore and migrates toward the centrosomes.Taken together,this evidence strongly supports a model in which TTK functions in spindle checkpoint signaling cascades at both kinetochore and centrosome.展开更多
目的:运用生物信息学方法筛选出鼻咽癌相关核心基因苏氨酸和酪氨酸激酶(threonine and tyrosine kinase,TTK),探讨其在鼻咽癌组织中的表达;敲低TTK对人鼻咽癌CNE2细胞生物学行为的影响及可能存在的机制。方法:利用生物信息学方法,基于GE...目的:运用生物信息学方法筛选出鼻咽癌相关核心基因苏氨酸和酪氨酸激酶(threonine and tyrosine kinase,TTK),探讨其在鼻咽癌组织中的表达;敲低TTK对人鼻咽癌CNE2细胞生物学行为的影响及可能存在的机制。方法:利用生物信息学方法,基于GEO数据库中鼻咽癌患者数据集,筛选出与鼻咽癌发生发展相关核心基因TTK;免疫组化实验检测TTK在鼻咽癌组织和慢性鼻咽炎组织中的表达;慢病毒转染人鼻咽癌CNE2细胞敲低TTK后,CCK-8实验检测敲低TTK对CNE2细胞增殖的影响;流式细胞实验检测TTK低表达后对CNE2细胞凋亡及周期的影响;Western Blot实验检测CNE2细胞在TTK低表达时,凋亡信号通路中关键蛋白BCL-2、BAX蛋白表达情况,探究TTK在鼻咽癌发生发展中可能存在的机制。结果:生物信息学方法筛选出核心基因TTK。TTK在鼻咽癌组织中呈现高表达,在慢性鼻咽炎组织中呈现低表达。敲低TTK后,CNE2细胞增殖受到抑制,细胞凋亡增加。细胞周期G_(1)期减少且S期和G_(2)期增加,提示敲低TTK导致细胞阻滞于S/G_(2)期。TTK的沉默导致CNE2细胞中BCL-2蛋白表达下降,BAX蛋白表达升高。结论:TTK在鼻咽癌组织中高表达。敲低TTK影响鼻咽癌CNE2细胞的增殖、凋亡、周期和凋亡通路关键蛋白BCL-2、BAX的表达,表明TTK可能通过凋亡通路参与鼻咽癌的发生发展。展开更多
苏氨酸和酪氨酸激酶(Threonine and tyrosine kinase,TTK)是纺锤体组装检查点的核心成分,许多研究发现TTK抑制剂可用于恶性肿瘤的治疗,在一些恶性肿瘤中可以与放化疗相结合提高治疗效果,并且TTK可以作为独立的生物标志物提示预后。本文...苏氨酸和酪氨酸激酶(Threonine and tyrosine kinase,TTK)是纺锤体组装检查点的核心成分,许多研究发现TTK抑制剂可用于恶性肿瘤的治疗,在一些恶性肿瘤中可以与放化疗相结合提高治疗效果,并且TTK可以作为独立的生物标志物提示预后。本文对TTK抑制剂及其与放化疗联合应用于肿瘤治疗和TTK对肿瘤预后预测的研究进展进行综述。展开更多
Spindle checkpoint is an important biochemical signaling cascade during mitosis which monitors the fidelity of chromosome segregation, and is mediated by protein kinases Mpsl and Bubl/BubRl. Our recent studies show th...Spindle checkpoint is an important biochemical signaling cascade during mitosis which monitors the fidelity of chromosome segregation, and is mediated by protein kinases Mpsl and Bubl/BubRl. Our recent studies show that kinesin-related motor protein CENP-E interacts with BubRl and participates in spindle checkpoint signaling. To elucidate the molecular mechanisms underlying spindle checkpoint signaling, we carried out proteomic dissection of human cell kinetochore and revealed protein kinase TTK, human homologue of yeast Mpsl. Our studies show that TTK is localized to the kinetochore of human cells, and interacts with CENP-E, suggesting that TTK may play an important role in chromosome segregation during mitosis.展开更多
基金supported by grants from the Chinese Outstanding Young Scientist Award(39925018)the Chinese Academy of Science(KSCX2-2-01)+1 种基金the Chinese 973 project(2002CB713700)the American Cancer Society(RPG59282)to XY.
文摘Entry into mitosis is driven by signaling cascades of mitotic kinases.Our recent studies show that TTK,a kinetochore-associated protein kinase,interacts with CENP-E,a mitotic kinesin located to corona fiber ofkinetochore.Using immunoelectron microscopy,here we show that TTK is present at the nuclear pore adjacent complex of interphase HeLa cells.Upon nuclear envelope fragmentation,TTK targets to the outermostregion of the developing kinetochores ofmonoorient chromosome as well as to spindle poles.After stable attachment,throughout chromosome congression,TTK is a constituent of the corona fibers,extending up to 90 nm away from the kinetochore outer plate.Upon metaphase alignment,TTK departs from the kinetochore and migrates toward the centrosomes.Taken together,this evidence strongly supports a model in which TTK functions in spindle checkpoint signaling cascades at both kinetochore and centrosome.
文摘目的:运用生物信息学方法筛选出鼻咽癌相关核心基因苏氨酸和酪氨酸激酶(threonine and tyrosine kinase,TTK),探讨其在鼻咽癌组织中的表达;敲低TTK对人鼻咽癌CNE2细胞生物学行为的影响及可能存在的机制。方法:利用生物信息学方法,基于GEO数据库中鼻咽癌患者数据集,筛选出与鼻咽癌发生发展相关核心基因TTK;免疫组化实验检测TTK在鼻咽癌组织和慢性鼻咽炎组织中的表达;慢病毒转染人鼻咽癌CNE2细胞敲低TTK后,CCK-8实验检测敲低TTK对CNE2细胞增殖的影响;流式细胞实验检测TTK低表达后对CNE2细胞凋亡及周期的影响;Western Blot实验检测CNE2细胞在TTK低表达时,凋亡信号通路中关键蛋白BCL-2、BAX蛋白表达情况,探究TTK在鼻咽癌发生发展中可能存在的机制。结果:生物信息学方法筛选出核心基因TTK。TTK在鼻咽癌组织中呈现高表达,在慢性鼻咽炎组织中呈现低表达。敲低TTK后,CNE2细胞增殖受到抑制,细胞凋亡增加。细胞周期G_(1)期减少且S期和G_(2)期增加,提示敲低TTK导致细胞阻滞于S/G_(2)期。TTK的沉默导致CNE2细胞中BCL-2蛋白表达下降,BAX蛋白表达升高。结论:TTK在鼻咽癌组织中高表达。敲低TTK影响鼻咽癌CNE2细胞的增殖、凋亡、周期和凋亡通路关键蛋白BCL-2、BAX的表达,表明TTK可能通过凋亡通路参与鼻咽癌的发生发展。
文摘苏氨酸和酪氨酸激酶(Threonine and tyrosine kinase,TTK)是纺锤体组装检查点的核心成分,许多研究发现TTK抑制剂可用于恶性肿瘤的治疗,在一些恶性肿瘤中可以与放化疗相结合提高治疗效果,并且TTK可以作为独立的生物标志物提示预后。本文对TTK抑制剂及其与放化疗联合应用于肿瘤治疗和TTK对肿瘤预后预测的研究进展进行综述。
基金This work was supported in part by the National Natural Science Foundation of China(Grant No.39925018)the Key Project of the Chinese Academy of Sciences(Grant No.KSCX2-2-01).
文摘Spindle checkpoint is an important biochemical signaling cascade during mitosis which monitors the fidelity of chromosome segregation, and is mediated by protein kinases Mpsl and Bubl/BubRl. Our recent studies show that kinesin-related motor protein CENP-E interacts with BubRl and participates in spindle checkpoint signaling. To elucidate the molecular mechanisms underlying spindle checkpoint signaling, we carried out proteomic dissection of human cell kinetochore and revealed protein kinase TTK, human homologue of yeast Mpsl. Our studies show that TTK is localized to the kinetochore of human cells, and interacts with CENP-E, suggesting that TTK may play an important role in chromosome segregation during mitosis.
