B-type plexins regulate mitosis via RanGTPase.

IF 4.1 2区医学 Q2 CELL BIOLOGY

Molecular Cancer Research Pub Date : 2024-08-13 DOI:10.1158/1541-7786.MCR-23-0836

Nicholus Mukhwana, Ritu Garg, Alexandria R Mitchell, Abul Azad, Magali Williamson

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引用次数: 0

Abstract

Aberrant mitosis can result in aneuploidy and cancer. The small GTPase, Ran, is a key regulator of mitosis. B-type Plexins regulate Ran activity by acting as RanGTPase activating proteins (GAPs) and have been implicated in cancer progression. However, whether B-type plexins have a role in mitosis has not so far been investigated. We show here that PlexinB1 functions in the control of mitosis. Depletion of PlexinB1 affects mitotic spindle assembly, significantly delaying anaphase. This leads to mitotic catastrophe in some cells, and prolonged application of the spindle assembly checkpoint. PlexinB1 depletion also promoted acentrosomal microtubule nucleation and defects in spindle pole refocussing and increased the number of cells with multipolar or aberrant mitotic spindles. An increase in lagging chromosomes or chromosomal bridges at anaphase was also found upon PlexinB1 depletion. PlexinB1 localises to the mitotic spindle in dividing cells. The mitotic defects observed upon PlexinB1 depletion were rescued by an RCC1 inhibitor, indicating that PlexinB1 signals, via Ran, to affect mitosis. These errors in mitosis generated multinucleate cells, and nuclei of altered morphology and abnormal karyotype. Furthermore, Semaphorin4D-treatment increased the percentage of cells with micronuclei, precursors of chromothripsis. Implications: Defects in B-type plexins may contribute to the well-established role of plexins in cancer progression by inducing chromosomal instability.

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B 型丛集蛋白通过 RanGTPase 调节有丝分裂。

有丝分裂异常可导致非整倍体和癌症。小 GTP 酶 Ran 是有丝分裂的关键调节因子。B 型丛集蛋白通过作为 RanGTPase 激活蛋白（GAPs）来调节 Ran 的活性，并与癌症进展有牵连。然而，B 型丛集蛋白是否在有丝分裂中发挥作用，迄今为止尚未有研究。我们在此证明了 PlexinB1 在控制有丝分裂中的功能。PlexinB1的耗竭会影响有丝分裂纺锤体的组装，明显延迟无丝分裂。这导致一些细胞出现有丝分裂灾难，并延长了纺锤体组装检查点的应用时间。消耗 PlexinB1 还会促进顶体微管成核和纺锤极重新聚焦缺陷，并增加多极或异常有丝分裂纺锤的细胞数量。PlexinB1缺失后，无丝分裂期的滞后染色体或染色体桥也会增加。PlexinB1 定位于分裂细胞中的有丝分裂纺锤体。在 PlexinB1 缺失时观察到的有丝分裂缺陷被 RCC1 抑制剂所挽救，这表明 PlexinB1 通过 Ran 发出信号影响有丝分裂。有丝分裂中的这些错误产生了多核细胞、形态改变的细胞核和异常核型。此外，Semaphorin4D 处理还增加了染色体三分裂前体--微核细胞的比例。影响：B型丛集蛋白缺陷可能会诱导染色体不稳定性，从而导致丛集蛋白在癌症进展过程中发挥公认的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.