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PLoS Biol:细胞分裂关键蛋白的确认有助癌症药物研发

近来,来自爱丁堡大学的研究人员在PLoS Biology杂志上发表文章称:他们在细胞分裂上有了新的认识,明确了调控细胞分裂的两个关键蛋白的作用方式。

当正常细胞增殖失去控制的时候,过度增殖会引发细胞癌变导致肿瘤的发生,这项研究可能对开发抑制肿瘤细胞增殖发挥抗肿瘤的药物意义非常大。

研究人员将这种能抑制肿瘤细胞增殖的潜在开发药物称为“有丝分裂拮抗药”,这些拮抗药将有可能改善癌症患者接受化疗后带来的相关副作用如化疗会损伤正常神经细胞。这类拮抗药物的研发可以帮助优化癌症病人的个性化化疗。

为了搞清楚参与细胞分裂过程的各种蛋白质在细胞内如何相互作用,研究人员运用高分辨率显微镜观察了细胞的三维形态,确定了参与调控细胞分裂的各种蛋白质的具体位置,同时也确定了调控细胞增殖的一个关键的蛋白质如何结合并激活分裂过程中两个关键酶。早期研究已证明了这两个酶是研发抗肿瘤药物的靶点,最新的发现使得科学家明确了如何制造更好的药物来阻止两种酶的活性。

该研究主要领导人--爱丁堡大学生物科学学院Mar Carmena教授称:正常细胞的分裂过程是一个复杂并严格受控制的过程,一旦这一平衡被打破的话,细胞增殖将失控导致癌症的发生。我们只有对调控细胞增殖的蛋白质有了充分的了解,才能设计出更有效的癌症治疗措施。(生物谷 Bioon.com)


参考文献:


The Chromosomal Passenger Complex Activates Polo Kinase at Centromeres

DOI:doi:10.1371/journal.pbio.1001250
AUTHORS:Mar Carmena1*, Xavier Pinson2, Melpi Platani1, Zeina Salloum2, Zhenjie Xu1, Anthony Clark1, Fiona MacIsaac1,et al.
ABSTRACT:The coordinated activities at centromeres of two key cell cycle kinases, Polo and Aurora B, are critical for ensuring that the two sister kinetochores of each chromosome are attached to microtubules from opposite spindle poles prior to chromosome segregation at anaphase. Initial attachments of chromosomes to the spindle involve random interactions between kinetochores and dynamic microtubules, and errors occur frequently during early stages of the process. The balance between microtubule binding and error correction (e.g., release of bound microtubules) requires the activities of Polo and Aurora B kinases, with Polo promoting stable attachments and Aurora B promoting detachment. Our study concerns the coordination of the activities of these two kinases in vivo. We show that INCENP, a key scaffolding subunit of the chromosomal passenger complex (CPC), which consists of Aurora B kinase, INCENP, Survivin, and Borealin/Dasra B, also interacts with Polo kinase in Drosophila cells. It was known that Aurora A/Bora activates Polo at centrosomes during late G2. However, the kinase that activates Polo on chromosomes for its critical functions at kinetochores was not known. We show here that Aurora B kinase phosphorylates Polo on its activation loop at the centromere in early mitosis. This phosphorylation requires both INCENP and Aurora B activity (but not Aurora A activity) and is critical for Polo function at kinetochores. Our results demonstrate clearly that Polo kinase is regulated differently at centrosomes and centromeres and suggest that INCENP acts as a platform for kinase crosstalk at the centromere. This crosstalk may enable Polo and Aurora B to achieve a balance wherein microtubule mis-attachments are corrected, but proper attachments are stabilized allowing proper chromosome segregation.

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