The role of a mitotic gene expression for the function of the mitotic spindle assembly checkpoint

有丝分裂纺锤体组装检查点控制着有丝分裂过程中姐妹染色单体的准确分离。除了它的作用，以确保染色体的稳定性，该信号通路也是必不可少的中介诱导细胞的凋亡，以回应针对有丝分裂纺锤体的化疗药物。纺锤体检查点缺陷在人类癌症中很常见，可导致染色体不稳定和对化疗产生抵抗力，但癌细胞中纺锤体检查点失活的机制在很大程度上尚不清楚。有趣的是，我们的结果表明，尽管全球基因表达被关闭，但纺锤体检查点的活动在有丝分裂过程中需要活跃的转录和翻译。我们已经分别确定了参与纺锤体检查点的基因和mRNA，该检查点可能受到有丝分裂转录和翻译的影响。在这项研究方案中，我们希望确定在纺锤体检查点介导的有丝分裂停止过程中活跃表达的其他基因和mRNAs。此外，我们想要证明它们的有丝分裂表达及其生理意义。此外，我们希望通过研究有丝分裂过程中启动子调控和5‘-帽独立但IRES(内部核糖进入位点)依赖的mRNA翻译来研究有丝分裂基因表达的分子机制。有丝分裂基因表达的失控可能是有丝分裂纺锤体检查点功能失活导致染色体不稳定和化疗耐药的重要机制。

The mitotic spindle assembly checkpoint controls the accurate segregation of sister chromatids during mitosis. In addition to its role to ensure chromosomal stability this signaling pathway is also essential to mediate the induction of apoptosis in response to chemotherapeutic drugs targeting the mitotic spindle. Defects in the spindle checkpoint are frequent in human cancer and can confer chromosomal instability and resistance towards chemotherapy, but the mechanisms of spindle checkpoint inactivation in cancer cells are largely unknown. Interestingly, our results show that the activity of the spindle checkpoint requires active transcription and translation during mitosis despite the fact that global gene expression is turned off. We have identified a gene and a mRNA, respectively, that participates in the spindle checkpoint, which might be subject to mitotic transcription and translation. In this research proposal we would like to identify additional genes and mRNAs that are actively expressed during a spindle checkpoint mediated mitotic arrest. Further, we want to demonstrate their mitotic expression and the physiological significance thereof. Additionally, we would like to address the molecular mechanisms of the mitotic gene expression by investigating promotor regulation and 5´-cap independent, but IRES (internal ribose entry site) dependent mRNA translation during mitosis. A deregulated mitotic gene expression might be an important mechanism of a functional inactivation of the mitotic spindle checkpoint leading to chromosomal instability and chemotherapy resistance.