Baron Anna P, von Schubert Conrad, Cubizolles Fabien, Siemeister Gerhard, Hitchcock Marion, Mengel Anne, Schröder Jens, Fernández-Montalván Amaury, von Nussbaum Franz, Mumberg Dominik, Nigg Erich A
Biozentrum, University of Basel, Basel, Switzerland.
Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
Elife. 2016 Feb 17;5:e12187. doi: 10.7554/eLife.12187.
The kinase Bub1 functions in the spindle assembly checkpoint (SAC) and in chromosome congression, but the role of its catalytic activity remains controversial. Here, we use two novel Bub1 inhibitors, BAY-320 and BAY-524, to demonstrate potent Bub1 kinase inhibition both in vitro and in intact cells. Then, we compared the cellular phenotypes of Bub1 kinase inhibition in HeLa and RPE1 cells with those of protein depletion, indicative of catalytic or scaffolding functions, respectively. Bub1 inhibition affected chromosome association of Shugoshin and the chromosomal passenger complex (CPC), without abolishing global Aurora B function. Consequently, inhibition of Bub1 kinase impaired chromosome arm resolution but exerted only minor effects on mitotic progression or SAC function. Importantly, BAY-320 and BAY-524 treatment sensitized cells to low doses of Paclitaxel, impairing both chromosome segregation and cell proliferation. These findings are relevant to our understanding of Bub1 kinase function and the prospects of targeting Bub1 for therapeutic applications.
激酶Bub1在纺锤体组装检查点（SAC）和染色体排列过程中发挥作用，但其催化活性的作用仍存在争议。在此，我们使用两种新型Bub1抑制剂BAY - 320和BAY - 524，证明其在体外和完整细胞中均能有效抑制Bub1激酶。然后，我们比较了HeLa和RPE1细胞中Bub1激酶抑制的细胞表型与蛋白质缺失的细胞表型，后者分别指示催化或支架功能。抑制Bub1会影响守护蛋白和染色体乘客复合体（CPC）与染色体的结合，但不会消除整体极光激酶B（Aurora B）的功能。因此，抑制Bub1激酶会损害染色体臂的分离，但对有丝分裂进程或SAC功能仅产生轻微影响。重要的是，用BAY - 320和BAY - 524处理会使细胞对低剂量紫杉醇敏感，损害染色体分离和细胞增殖。这些发现有助于我们理解Bub1激酶的功能以及将Bub1作为治疗靶点的前景。
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