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Pim-1 associates with protein complexes necessary for mitosis

机译：Pim-1与有丝分裂所必需的蛋白质复合物相关

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摘要

The proto-oncogene pim-1 is a serine/threonine kinase the over-expression of which promotes lymphoma formation. Neither the normal function of Pim-1 nor the biochemical mechanism for cancer development mediated by the gene has been delineated, although recent studies have provided compelling evidence that Pim-1 is involved in differentiation and cell survival. We now provide the first evidence that Pim-1 may be involved in the proliferative process. By confocal microscopy, we observed a dynamic redistribution of Pim-1 during the cell cycle, the protein moving from the nucleus and cytoplasm in interphase to the spindle poles during mitosis. From a computer search for putative substrates of Pim-1 that are located in the spindle poles, we discovered that the nuclear mitotic apparatus (NuMA) protein has two peptide sequences that contain preferred phosphorylation sites for Pim-1 kinase. Recombinant glutathione-S-transferase-Pim-1 also readily phosphorylates immunoprecipitated NuMA. By confocal microscopy and co-immunoprecipitation we showed the interaction of the Pim-1 and NuMA proteins in HeLa cells that had been arrested during mitosis with nocodazole. Pim-1 also appeared to interact with heterochromatin-associated protein 1β (HP1β) and the cytoplasmic proteins dynein and dynactin via complex formation with NuMA. In our studies, overexpressed wild-type-Pim-1-GFP (green fluorescent protein) fusion protein was found to co-localize in the spindle pole with NuMA during mitosis. In contrast, the 'kinase-dead' mut-Pim-1-GFP fusion protein did not co-localize with NuMA, and appeared to promote apoptosis. Further evidence for apoptotic cell death was the observed blebbing and fragmentation of the chromosomes and a decrease in the level of NuMA protein detected by confocal microscopy. These results strongly suggest that Pim-1 kinase plays a role, most likely by phosphorylation, in promoting complex formation between NuMA, HP1β, dynein and dynactin, a complex that is necessary for mitosis.
机译：原癌基因pim-1是丝氨酸/苏氨酸激酶，其过度表达可促进淋巴瘤的形成。虽然最近的研究已经提供了令人信服的证据表明Pim-1参与了分化和细胞存活，但Pim-1的正常功能或由该基因介导的癌症发展的生化机制都没有被描述。我们现在提供第一个证据，证明Pim-1可能参与了增殖过程。通过共聚焦显微镜，我们观察到了Pim-1在细胞周期中的动态重新分布，蛋白质在有丝分裂过程中从细胞核和细胞质在相间移动到纺锤体极。通过计算机搜索位于纺锤极中的Pim-1的假定底物，我们发现核有丝分裂装置（NuMA）蛋白具有两个肽序列，其中包含Pim-1激酶的优选磷酸化位点。重组谷胱甘肽-S-转移酶-Pim-1也容易磷酸化免疫沉淀的NuMA。通过共聚焦显微镜和免疫共沉淀，我们显示了在有丝分裂期间被诺考达唑阻滞的HeLa细胞中Pim-1和NuMA蛋白的相互作用。 Pim-1还似乎通过与NuMA形成复合物而与异染色质相关蛋白1β（HP1β）和细胞质蛋白dynein和dynactin相互作用。在我们的研究中，发现有丝分裂期间过表达的野生型Pim-1-GFP（绿色荧光蛋白）融合蛋白与NuMA共同定位在纺锤极中。相反，“激酶死亡”的mut-Pim-1-GFP融合蛋白未与NuMA共定位，并且似乎促进了细胞凋亡。细胞凋亡的进一步证据是观察到的染色体起泡和断裂以及通过共聚焦显微镜检测到的NuMA蛋白水平的降低。这些结果强烈表明，Pim-1激酶最有可能通过磷酸化作用来促进NuMA，HP1β，动力蛋白和动力蛋白之间的复合物形成，这是有丝分裂所必需的复合物。

著录项

  • 来源
    《Chromosoma》 |2002年第2期|80-95|共16页
  • 作者

    Nandini Bhattacharya; Zeping Wang; Christine Davitt; Ian F. McKenzie; Pei-xiang Xing; Nancy S. Magnuson;

  • 作者单位

    School of Molecular Biosciences WSU Pullman WA 99164-4234 USA;

    School of Molecular Biosciences WSU Pullman WA 99164-4234 USA;

    The Electron Microscopy Center School of Biological Sciences WSU Pullman WA 99164-4234 USA;

    The Austin Research Institute Victoria Australia;

    The Austin Research Institute Victoria Australia;

    School of Molecular Biosciences WSU Pullman WA 99164-4234 USA;

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