Bone morphogenetic protein (BMP) signaling regulates mitotic checkpoint protein levels in human breast cancer cells.
Bone morphogenetic protein (BMP) signaling regulates mitotic checkpoint protein levels in human breast cancer cells.
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DOI：
10.1016/j.cellsig.2011.12.019
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发表时间：
2012-04
影响因子：
4.8
通讯作者：
Hualong Yan;Songcheng Zhu;Chenlin Song;Nai-fa Liu;Jiuhong Kang
中科院分区：
文献类型：
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作者：
Hualong Yan;Songcheng Zhu;Chenlin Song;Nai-fa Liu;Jiuhong Kang
有丝分裂检查点基因的异常表达破坏了有丝分裂检查点，导致染色体不稳定和肿瘤发生。然而，控制有丝分裂检查点基因表达的细胞信号至今未见报道。在本研究中，我们表明，在人乳腺癌细胞中，骨形态发生蛋白（BMP）的化学抑制，而不是转化生长因子-β（TGF-β），消除了诺考达唑诱导的有丝分裂阻滞。蛋白质表达分析显示，BMP信号传导的抑制显著下调有丝分裂检查点组分BUB 3、Hec 1、TTK和MAD 2的蛋白质水平，但TGF-β的抑制对这些蛋白质的表达具有相对较小的影响。BMP信号的激活特异性地上调BUB 3，而激活素A信号的激活全面下调这些蛋白质水平。此外，过表达MAD 2、TTK、BUB 3或Hec 1显著地挽救了由BMP抑制引起的有丝分裂停滞缺陷。我们的研究结果首次证明了TGF-β家族细胞因子是调节有丝分裂检查点的细胞信号，并且内在BMP信号传导的扰动可以通过下调关键检查点蛋白而导致有丝分裂检查点信号传导的抑制。这些结果提示了一种可能的机制，通过这种机制，TGF-β信号传导的失调导致有丝分裂检查点缺陷并驱动肿瘤发生。这一发现也为通过靶向BMP和有丝分裂检查点连接来预防癌症提供了一种潜在的和更特异的策略。
Aberrant expression of mitotic checkpoint genes compromises mitotic checkpoint, leads to chromosome instability and tumorigenesis. However, the cell signals that control mitotic checkpoint gene expression have not been reported so far. In the present study we show that, in human breast cancer cells, chemical inhibition of Bone morphogenetic proteins (BMPs), but not Transforming Growth Factor-β (TGF-β), abrogates the mitotic arrest induced by nocodazole. Protein expression analysis reveals that inhibition of BMP signaling dramatically down regulates protein levels of mitotic checkpoint components BUB3, Hec1, TTK and MAD2, but inhibition of TGF-β has relatively minor effect on the expression of these proteins. Activation of BMP signaling specifically up regulates BUB3, and activation of Activin A signaling globally down regulates these proteins level. Furthermore, overexpressing MAD2, TTK, BUB3 or Hec1 significantly rescues the mitotic arrest defect caused by BMP inhibition. Our results demonstrated for the first time that TGF-β family cytokines are cellular signals regulating mitotic checkpoint and perturbations in intrinsic BMP signaling could lead to suppression of mitotic checkpoint signaling by downregulating key checkpoint proteins. The results suggest a possible mechanism by which dysregulation of TGF-β signaling causes mitotic checkpoint defects and drives tumorigenesis. The finding also provides a potential and more specific strategy for cancer prevention by targeting BMP and mitotic checkpoint connection.