Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase.
Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase.
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DOI：
10.1002/ijc.25954
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发表时间：
2011-08-01
影响因子：
6.4
通讯作者：
Mulder, Kathleen M.
中科院分区：
文献类型：
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作者：
Pulipati, Nageswara R.;Jin, Qunyan;Liu, Xin;Sun, Baodong;Zhao, Yan;Pandey, Manoj K.;Huber, Jonathan P.;Ding, Wei;Mulder, Kathleen M.
km23-1 是一种动力蛋白轻链，被鉴定为 TGFβ 受体相互作用蛋白。为了研究 km23-1 是否控制人卵巢癌细胞 (HOCC) 生长，我们在 SKOV-3 细胞中建立了 tet-off 诱导表达系统，其中去除强力霉素后可诱导 km23-1 的表达。我们发现 km23-1 的强制表达抑制 SKOV-3 细胞的贴壁依赖性和贴壁非依赖性生长。更重要的是，在体内异种移植模型中，km23-1表达的诱导显着降低了SKOV-3细胞的致瘤性。 SKOV-3 和 IGROV-1 HOCC 的荧光激活细胞分选分析表明，细胞在 G2/M 时积累。 Phospho-MEK、磷酸-ERK 和细胞周期蛋白 B1 升高，有丝分裂指数升高，表明 km23-1 通过诱导有丝分裂延迟来抑制 HOCC 生长。免疫荧光分析表明，细胞在中期/中期积累，多极和多核细胞增加。此外，虽然有丝分裂纺锤体组装检查点蛋白 BubR1 存在于 Dox+/- 细胞的中期着丝粒处，但它不适当地保留在 Dox− 细胞的中期着丝粒处。因此，高水平的km23-1在体外抑制卵巢癌生长并在体内抑制卵巢肿瘤形成的机制似乎涉及BubR1相关的有丝分裂延迟。
km23-1 is a dynein light chain that was identified as a TGFß receptor-interacting protein. To investigate whether km23-1 controls human ovarian carcinoma cell (HOCC) growth, we established a tet-off inducible expression system in SKOV-3 cells in which the expression of km23-1 is induced upon doxycycline removal. We found that forced expression of km23-1 inhibited both anchorage-dependent and anchorage-independent growth of SKOV-3 cells. More importantly, induction of km23-1 expression substantially reduced the tumorigenicity of SKOV-3 cells in a xenograft model in vivo. Fluorescence-activated cell sorting analysis of SKOV-3 and IGROV-1 HOCCs demonstrated that the cells were accumulating at G2/M. Phospho-MEK, phospho-ERK, and cyclin B1 were elevated, as was the mitotic index, suggesting that km23-1 suppresses HOCCs growth by inducing a mitotic delay. Immunofluorescence analyses demonstrated that the cells were accumulating at prometaphase/metaphase with increases in multipolar and multinucleated cells. Further, while the mitotic spindle assembly checkpoint protein BubR1 was present at the prometaphase kinetochore in Dox+/− cells, it was inappropriately retained at the metaphase kinetochore in Dox− cells. Thus, the mechanism by which high levels of km23-1 suppresses ovarian carcinoma growth in vitro and inhibits ovary tumor formation in vivo appears to involve a BubR1-related mitotic delay.
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影响因子：
8
作者：
Jeffery, J. M.;Urquhart, A. J.;Khanna, K. K.
通讯作者：
Khanna, K. K.
影响因子：
3.5
作者：
Jiang, JM;Yu, L;Zhao, SY
通讯作者：
Zhao, SY
影响因子：
4.8
作者：
Jin, Qunyan;Ding, Wei;Mulder, Kathleen M.
通讯作者：
Mulder, Kathleen M.
影响因子：
8
作者：
Li, S.;Szymborski, A.;Branton, P. E.
通讯作者：
Branton, P. E.
DOI：
10.1038/nrm2804
发表时间：
2009-12
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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