bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–03–09
ten papers selected by
Valentina Piano, Uniklinik Köln



  1. EMBO J. 2025 Mar 03.
      Polo-like kinase 1 (PLK1) is a conserved regulator of cell division. During mitotic prophase, PLK1 contributes to the activation of the cyclin-dependent kinase 1 (CDK1). However, the exact functions of PLK1 in prophase remain incompletely understood. Here, we show that PLK1 inhibition in synchronous G2 cell populations of multiple mammalian cell lines delays or prevents mitotic entry with high variability between individual cells. Using a mathematical model, we recapitulate this phenomenon and provide an explanation for the observed phenotypic variability. We show that PLK1-inhibited cells are delayed in a prophase-like state with low CDK1 activity that increases slowly and gradually over hours. These cells display progressively condensing chromosomes, increased microtubule dynamics, and reorganization of the actin cortex, while the nuclear envelope remains intact. We characterize this state further by phosphoproteomics, revealing phosphorylation of regulators of chromatin organization and the cytoskeleton consistent with the cellular phenotypes. Together, our results indicate that PLK1 inhibition stabilizes cells in a prophase-like state with low CDK1 activity displaying a specific set of early mitotic phosphorylation events.
    Keywords:  Cell Cycle; Mitosis; Mitotic Entry; Phosphoproteomics; Polo-like Kinase 1
    DOI:  https://doi.org/10.1038/s44318-025-00400-9
  2. PLoS One. 2025 ;20(3): e0315751
      Akt3 is a key regulator of mitochondrial homeostasis in the endothelium. Akt3 depletion results in mitochondrial dysfunction, decreased mitochondrial biogenesis, and decreased angiogenesis. Here we link mitochondrial homeostasis with mitotic fidelity-depletion of Akt3 results in the missegregation of chromosomes as visualized by multinucleation and micronuclei formation. We have connected Akt3 to Aurora B, a significant player in chromosome segregation. Akt3 localizes to the nucleus, where it associates with and regulates WDR12. During mitosis, WDR12 is localized to the dividing chromosomes, and its depletion results in a similar mitotic phenotype to Akt3 depletion. WDR12 associates with Aurora B, both of which are downregulated under conditions of Akt3 depletion. We used the model oxidant paraquat to induce mitochondrial dysfunction to test whether the Akt3-dependent effect on mitochondrial homeostasis is linked to mitotic function. Paraquat treatment also causes chromosome missegregation by inhibiting the expression of Akt3, WDR12, and Aurora B. The inhibition of ROS rescued both the mitotic fidelity and the expression of Akt3 and Aurora B. Akt3 directly phosphorylates the major nuclear export protein CRM-1, causing an increase in its expression, resulting in the inhibition of PGC-1 nuclear localization, the master regulator of mitochondrial biogenesis. The Akt3/Aurora B pathway is also dependent on CRM-1. CRM-1 overexpression resulted in chromosome missegregation and downregulation of Aurora B similar to that of Akt3 depletion. Akt3 null hearts at midgestation (E14.5), a stage in which proliferation is occurring, have decreased Aurora B expression, increased CRM-1 expression, decreased proliferation, and increased apoptosis. Akt3 null hearts are smaller and have a thinner compact cell layer than age-matched wild-type mice. Akt3 null tissue has dysmorphic nuclear structures, suggesting mitotic catastrophe. Our findings show that mitochondrial dysfunction induced by paraquat or Akt3 depletion results in a CRM-1-dependent disruption of Aurora B and mitotic fidelity.
    DOI:  https://doi.org/10.1371/journal.pone.0315751
  3. bioRxiv. 2025 Feb 17. pii: 2025.02.16.638494. [Epub ahead of print]
      MCAK/Kif2C is a microtubule-depolymerizing kinesin that is implicated in the correction of chromosome attachment errors. When this protein is eliminated from kinetochores, cells exhibit delayed congression and a modest increase in chromosome mis-segregation. Curiously, MCAK/Kif2C overexpression (OE) promotes these same defects. These mitotic delays are restricted to prometaphase and can be rescued by modulating MCAK/Kif2C activity solely at the centromere. Both excessive depletion and surplus levels of centromeric MCAK/Kif2C increased inter-kinetochore distances (IKDs) commensurate with an increase in acetylated tubulin in the spindle, a readout for k-fiber stability. Because both high and low levels of centromere-associated MCAK/Kif2C increased k-fiber stability, we conclude that this is the likely mechanism for the increased chromosome segregation errors observed in both these antagonistic conditions. Loss of centromeric MCAK/Kif2C delayed the conversion from lateral to end-on motility was delayed in MCAK/Kif2C-depleted cells. This likely represents the key activity that MCAK/Kif2C imparts to the centromere which, when present at consistently incorrect levels, slows k-fiber turnover and congression.
    DOI:  https://doi.org/10.1101/2025.02.16.638494
  4. Nat Commun. 2025 Mar 03. 16(1): 2116
      Primary constriction of the M-phase chromosome serves as a marker for the kinetochore position. Underlying this observation is the concept that the kinetochore is spatially linked with the pericentromere where sister-chromatids are cohered. Here, we find an unconventional chromatid-cohesion pattern in Peromyscus oocytes, with sister chromatids cohered at a chromosome end, spatially separated from the kinetochore. This distal locus enriches cohesin protectors specifically during meiosis, and chromosomes with this additional cohesion site exhibit enhanced cohesin protection at anaphase I compared to those without it, implying an adaptive evolution to ensure cohesion during meiosis. The distal locus corresponds to an additional centromeric satellite block, located far from the satellite block building the kinetochore. Analyses on three Peromyscus species reveal that the internal satellite consistently assembles the kinetochore in mitosis and meiosis, whereas the distal satellite selectively enriches cohesin protectors in meiosis to promote cohesion. Our study demonstrates that cohesion regulation is flexible, controlling chromosome segregation in a cell-type dependent manner.
    DOI:  https://doi.org/10.1038/s41467-025-57438-w
  5. Mol Biol Cell. 2025 Mar 05. mbcE24080382
      Protein phosphorylation regulates many steps in the cell division process including cytokinesis. In fission yeast cells, the anillin-like protein Mid1 sets the cell division plane and is regulated by phosphorylation. Multiple protein kinases act on Mid1, but no protein phosphatases have been shown to regulate Mid1. Here, we discovered that the conserved protein phosphatase PP2A-B56 is required for proper cytokinesis by promoting Mid1 protein levels. We find that par1∆ cells lacking the primary B56 subunit divide asymmetrically due to the assembly of misplaced cytokinetic rings that slide towards cell tips. These par1∆ mutants have reduced whole-cell levels of Mid1 protein, leading to reduced Mid1 at the cytokinetic ring. Restoring proper Mid1 expression suppresses par1∆ cytokinesis defects. This work identifies a new PP2A-B56 pathway regulating cytokinesis through Mid1, with implications for control of cytokinesis in other organisms.
    DOI:  https://doi.org/10.1091/mbc.E24-08-0382
  6. Tissue Cell. 2025 Feb 28. pii: S0040-8166(25)00091-6. [Epub ahead of print]94 102811
      The NIMA-related kinase (NEK) family of serine/threonine kinases is essential for the regulation of cell cycle progression, mitotic spindle assembly, and genomic stability. In this review, we explore the structural and functional diversity of NEK kinases, highlighting their roles in both canonical and non-canonical cellular processes. We examine recent preclinical findings on NEK inhibition, showcasing promising results for NEK-targeted therapies, particularly in cancer types characterized by high NEK expression. We discussed the therapeutic potential of targeting NEKs as modulators of cell cycle and DDR pathways, with a focus on identifying strategies to exploit NEK activity for enhanced treatment efficacy. Future research directions are proposed to further elucidate NEK-mediated mechanisms and to develop selective inhibitors that target NEK-related pathways.
    Keywords:  Genomic instability; Mitosis; Replication stress
    DOI:  https://doi.org/10.1016/j.tice.2025.102811
  7. Bioessays. 2025 Mar 03. e202500004
      Plant cytokinesis results in the formation of the cell plate by the phragmoplast which contains dynamic microtubules serving as the track for the delivery of cell wall builders included in Golgi vesicles. During the centrifugal process of cell plate assembly, new microtubules are assembled and bundled at the leading edge to prepare for vesicle transport while older microtubules are disassembled at the lagging edge upon the completion of vesicle delivery. The turnover of phragmoplast microtubules in this process is thought to be regulated by phosphorylation of the key microtubule bundling factor MAP65. A recent study revealed a surprising role of the α-Aurora kinase, which is typically known for its role in governing the formation of the bipolar spindle apparatus, in phosphorylating the primary microtubule bundler MAP65-3 in Arabidopsis. This phosphorylation positively contributes to the expansion of the phragmoplast. The phragmoplast midzone is also the hub for other cytokinesis-important kinases. It is intriguing how these kinases are targeted and how they may crosstalk with each other to orchestrate the expansion of the phragmoplast.
    DOI:  https://doi.org/10.1002/bies.202500004
  8. Artif Intell Med. 2025 Mar 03. pii: S0933-3657(25)00032-6. [Epub ahead of print]163 103097
      Mitosis detection is one of the fundamental tasks in computational pathology, which is extremely challenging due to the heterogeneity of mitotic cell. Most of the current studies solve the heterogeneity in the technical aspect by increasing the model complexity. However, lacking consideration of the biological knowledge and the complex model design may lead to the overfitting problem while limited the generalizability of the detection model. In this paper, we systematically study the morphological appearances in different mitotic phases as well as the ambiguous non-mitotic cells and identify that balancing the data and feature diversity can achieve better generalizability. Based on this observation, we propose a novel generalizable framework (MitDet) for mitosis detection. The data diversity is considered by the proposed diversity-guided sample balancing (DGSB). And the feature diversity is preserved by inter- and intra- class feature diversity-preserved module (InCDP). Stain enhancement (SE) module is introduced to enhance the domain-relevant diversity of both data and features simultaneously. Extensive experiments have demonstrated that our proposed model outperforms all the state-of-the-art (SOTA) approaches in several popular mitosis detection datasets in both internal and unseen test sets using point annotations only. Comprehensive ablation studies have also proven the effectiveness of the rethinking of data and feature diversity balancing. By analyzing the results quantitatively and qualitatively, we believe that our proposed model not only achieves SOTA performance but also might inspire the future studies in new perspectives. Code is available at https://github.com/linjiatai/MitDet.
    Keywords:  Computational pathology; Data and feature diversity; Mitosis detection; Model generalization
    DOI:  https://doi.org/10.1016/j.artmed.2025.103097
  9. Mol Biol Res Commun. 2025 ;14(2): 143-147
      Chromosome aberrations certainly aneuploidie are the cause of the majority of spontaneous abortions in humans. BUB1 (budding uninhibited by benzimidazole 1) and BUBR1 (BUB1 mitotic checkpoint serine/threonine kinase B) are two key proteins mediating spindle-checkpoint activation that play a role in the inhibition of the anaphase-promoting complex/ cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. This study aimed to evaluate the probable roles of BUB1 and BUBR1 pathogenic variants in abortion of the fetuses with aneuploidy. Fifty aborted fetuses with approved aneuploidy using array comparative genomic hybridization (aCGH) were included. BUB1 and BUBR1 genes were studied using the Sanger sequencing for the single nucleotide variant (SNV) detection, certainly rs121909055 and rs28989185 as the pathogenic target variants. The sequencing results were analyzed by finch TV software.Neither homozygous nor heterozygous variant of the targeted SNVs was observed in the samples. No other SNV was detectable in the analyzed parts of the BUB1 and BUBR1 genes in all samples. Since the allele frequencies of the variants of interest were zero in 50 studied samples, these SNVs would not be prioritized for screening in the parents with a history of miscarriage due to aneuploidy.
    Keywords:  Aneuploidy; BUB1; BUBR1; Spontaneous abortion
    DOI:  https://doi.org/10.22099/mbrc.2024.51170.2037
  10. Sci Rep. 2025 Mar 03. 15(1): 7382
      Analysis of cell populations and their behavior is very important in biological and medical research, such as tissue engineering and cancer research. Such behavioral analysis is often performed by visual observation of the cells using microscopy and other imaging techniques, which is often a time-consuming process due to the need for manual observations. Here, a fully automated mitotic event detection method has been developed allowing to reduce the processing time and improving the accuracy of the proliferation rate estimation of studied cell populations Despite the obvious morphological changes during mitosis, traditional image processing methods are not the best candidates, because some phenomena in the images appear as mitotic events but consist of noise and artifacts. These unwanted noise elements and artifacts can cause false positive detections and lead to low precision in detecting proliferation processes. Additionally, traditional cell imaging methods are based on single-cell segmentation resulting in lower performance for high cell densities. To minimize false positive detections, a machine learning-based modeling approach was developed and tested on two large datasets, one public dataset containing phase contrast images and another containing lens-free images. In the new method, traditional image processing, such as thresholding and cell tracking, is employed to select the candidate events. Next, the features that relate to the cell characteristics and process events are extracted. Before the classification step, features are selected using mutual information and ANOVA testing. Finally, false positive rejection is done using tree and random forest classifiers. The applied machine learning approach not only allows high processing performance but also explains how selected features contribute to mitotic event detection. The mean accuracy of the classifiers is 85.12% and precision and recall for the publicly available phase contrast dataset are 88.01% and 92.70% respectively. When applied to the lens-free image dataset, accuracy, precision, and recall were even higher and amounted to 87.66% 88.01%, and 91.78% respectively while employing much less features. The developed methodology has similar performance compared to the published deep learning approach, but has the advantage that it combines high performance with explainable features.
    DOI:  https://doi.org/10.1038/s41598-025-87180-8