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首页> 外文期刊>Cell cycle >Polo-like kinase 1 regulates activation of AMP-activated protein kinase (AMPK) at the mitotic apparatus.
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Polo-like kinase 1 regulates activation of AMP-activated protein kinase (AMPK) at the mitotic apparatus.

机译：Polo样激酶1调节有丝分裂装置上AMP激活的蛋白激酶（AMPK）的激活。

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AMP-activated protein kinase (AMPK) is being primarily studied as a central metabolic stress sensor, which regulates cell survival and growth-related metabolic pathways to preserve intracellular ATP levels in response to energy deprivation. Evidence is now accumulating that AMPK plays also an obligatory role to ensure proper cell division and faithful chromosomal segregation during mitosis. Increased phosphorylation in the AMPK catalytic subunit (AMPKalpha) was found in a proteomic study for kinases activated during G2/M and, more recently, activated AMPKalpha (PP-AMPKalpha(Thr172)) has been observed to transiently associate with several mitotic structures including centrosomes, spindle poles, the central spindle midzone and the midbody throughout all of the mitotic stages and cytokinesis. How AMPKalpha activation is controlled spatially and temporally during mitosis, however, remained undiscovered. Because Polo-like Kinases (PLKs) regulate many aspects of mitotic progression including centrosome maturation, bipolar spindle assembly, chromosome congression & segregation, and cytokinesis, we decided to combine an immunofluorescence microscopy analysis with a chemical biology approach employing a small-molecule PLK1 inhibitor to dissect a putative relationship between PLK1 and AMPKalpha during G2/M transition. PLK1 and PP-AMPKalpha(Thr172) were found to display a major spatio-temporal overlap early at centrosomes, from prophase until anaphase, and late at the midbody, during telophase and cytokinesis. Moreover, short-term treatment with the thiophene derivative GW843682X, a selective PLK inhibitor that has 400-fold greater potency for PLK1 than for PLK2 or PLK3, fully abolished mitotic activation of AMPKalpha. Upon long-term PLK1 inhibition, PP-AMPKalpha(Thr172) was barely detected surrounding the spindle poles of prometaphase-like arrested cells displaying the polo GW843682X-treated cells exhibiting cytokinesis failure and binucleate cell formation. Given that PLK1 is a well-recognized master regulatory kinase for the numerous protein substrates involved in mitosis, our current description of a causal link between PLK1 activity and mitotic phosphorylation of AMPKalpha may provide fundamental insights into how the energy sensor AMPK is directly coupled to mitotic cell division and cell cycle exist.
机译：AMP激活的蛋白激酶（AMPK）主要作为中央代谢应激传感器进行研究，该传感器调节细胞存活和与生长相关的代谢途径，以响应能量缺乏而保留细胞内ATP的水平。现在有证据表明，AMPK在有丝分裂过程中也起着确保正确的细胞分裂和忠实的染色体分离的作用。在蛋白质组学研究中，在G2 / M期间激活的激酶发现AMPK催化亚基（AMPKalpha）的磷酸化增加，最近，已发现激活的AMPKalpha（PP-AMPKalpha（Thr172））与包括中心体在内的几种有丝分裂结构瞬时缔合。 ，在所有有丝分裂阶段和胞质分裂过程中的纺锤体极点，中心纺锤体中间区和中体。然而，如何在有丝分裂期间如何在空间和时间上控制AMPKalpha激活尚未发现。由于Polo样激酶（PLKs）调控有丝分裂进程的许多方面，包括中心体成熟，双极纺锤体组装，染色体会聚和分离以及胞质分裂，因此我们决定将免疫荧光显微镜分析与采用小分子PLK1抑制剂的化学生物学方法相结合。剖析G2 / M过渡期间PLK1和AMPKalpha之间的推定关系。发现PLK1和PP-AMPKalpha（Thr172）在中心体早期，从前期到后期，到中体后期，在末期和胞质分裂中显示出主要的时空重叠。此外，使用噻吩衍生物GW843682X（一种选择性PLK抑制剂，对PLK1的效力比对PLK2或PLK3的效力高400倍）的短期治疗，完全消除了AMPKalpha的有丝分裂活化。在长期抑制PLK1后，几乎没有检测到PP-AMPKalpha（Thr172）围绕前中期样停滞细胞的纺锤极，显示经pololo GW843682X处理的细胞表现出胞质分裂失败和双核细胞形成。鉴于PLK1是参与有丝分裂的众多蛋白质底物的公认主调节激酶，因此，我们目前对PLK1活性与AMPKalpha的有丝分裂磷酸化之间因果关系的描述可能会提供有关能量传感器AMPK如何直接与有丝分裂耦合的基​​本见解。存在细胞分裂和细胞周期。

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