bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024–01–28
six papers selected by
Valentina Piano, Uniklinik Köln
  1. siRNA-Mediated BmAurora B Depletion Impedes the Formation of Holocentric Square Spindles in Silkworm Metaphase BmN4 Cells.
  2. Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition.
  3. Chromosomal passenger complex condensates generate parallel microtubule bundles in vitro.
  4. Atypical Mitotic Figures Are Prognostically Meaningful for Canine Cutaneous Mast Cell Tumors.
  5. Gross Chromosomal Rearrangement at Centromeres.
  6. Maximizing Anticancer Response with MPS1 and CENPE Inhibition Alongside Apoptosis Induction.
  1. Insects. 2024 Jan 19. pii: 72. [Epub ahead of print]15(1):
    siRNA-Mediated BmAurora B Depletion Impedes the Formation of Holocentric Square Spindles in Silkworm Metaphase BmN4 Cells.
    Bing Zhang, Camilo Ayra-Pardo, Xiaoning Liu, Meiting Song, Dandan Li, Yunchao Kan.
      Silkworm ovary-derived BmN4 cells rely on chromatin-induced spindle assembly to form microtubule-based square mitotic spindles that ensure accurate segregation of holocentric chromosomes during cell division. The chromosome passenger protein Aurora B regulates chromosomal condensation and segregation, spindle assembly checkpoint activation, and cytokinesis; however, its role in holocentric organisms needs further clarification. This study examined the architecture and dynamics of spindle microtubules during prophase and metaphase in BmN4 cells and those with siRNA-mediated BmAurora B knockdown using immunofluorescence labeling. Anti-α-tubulin and anti-γ-tubulin antibodies revealed faint γ-tubulin signals colocalized with α-tubulin in early prophase during nuclear membrane rupture, which intensified as prophase progressed. At this stage, bright regions of α-tubulin around and on the nuclear membrane surrounding the chromatin suggested the start of microtubules assembling in the microtubule-organizing centers (MTOCs). In metaphase, fewer but larger γ-tubulin foci were detected on both sides of the chromosomes. This resulted in a distinctive multipolar square spindle with holocentric chromosomes aligned at the metaphase plate. siRNA-mediated BmAurora B knockdown significantly reduced the γ-tubulin foci during prophase, impacting microtubule nucleation and spindle structure in metaphase. Spatiotemporal BmAurora B expression analysis provided new insights into the regulation of this mitotic kinase in silkworm larval gonads during gametogenesis. Our results suggest that BmAurora B is crucial for the formation of multipolar square spindles in holocentric insects, possibly through the activation of γ-tubulin ring complexes in multiple centrosome-like MTOCs.
    Keywords:  Bombyx mori; cell division; chromatin-induced spindle assembly; mitosis; siRNA
    DOI:  https://doi.org/10.3390/insects15010072
  2. EMBO J. 2024 Jan 26.
    Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition.
    Colin R Gliech, Zhong Y Yeow, Daniel Tapias-Gomez, Yuchen Yang, Zhaoyu Huang, Andréa E Tijhuis, Diana Cj Spierings, Floris Foijer, Grace Chung, Nuria Tamayo, Zahra Bahrami-Nejad, Patrick Collins, Thong T Nguyen, Andres Plata Stapper, Paul E Hughes, Marc Payton, Andrew J Holland.
      The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear. Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays. Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition. KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit.
    Keywords:  Anaphase Promoting Complex (APC/C); Cancer; KIF18A; Mitosis; Spindle Assembly Checkpoint (SAC)
    DOI:  https://doi.org/10.1038/s44318-024-00031-6
  3. J Biol Chem. 2024 Jan 23. pii: S0021-9258(24)00045-0. [Epub ahead of print] 105669
    Chromosomal passenger complex condensates generate parallel microtubule bundles in vitro.
    Ewa Niedzialkowska, Tan M Truong, Luke A Eldredge, Aamir Ali, Stefanie Redemann, P Todd Stukenberg.
      The mitotic spindle contains many bundles of microtubules (MT) including midzones and kinetochore fibers, but little is known about how bundled structures are formed. Here, we show that the Chromosomal Passenger Complex (CPC) purified from E. coli undergoes liquid-liquid demixing (LLD) in vitro. An emergent property of the resultant condensates is to generate parallel MT bundles when incubated with free tubulin and GTP in vitro. We demonstrate MT bundles emerge from CPC droplets with protruding minus-ends that then grow into long, tapered MT structures. During this growth, we found the CPC in these condensates apparently reorganize to coat and bundle the resulting MT structures. CPC mutants attenuated for LLD or MT binding prevented the generation of parallel MT bundles in vitro and reduced the number of MTs present at spindle midzones in HeLa cells. Our data demonstrate that an in vitro biochemical activity to produce microtubule bundles emerges after the concentration of the CPC and provides models for how cells generate parallel-bundled MT structures that are important for the assembly of the mitotic spindle. Moreover, these data suggest that cells contain microtubule organizing centers that generate microtubule bundles that emerge with the opposite polarity from centrosomes.
    DOI:  https://doi.org/10.1016/j.jbc.2024.105669
  4. Vet Sci. 2023 Dec 20. pii: 5. [Epub ahead of print]11(1):
    Atypical Mitotic Figures Are Prognostically Meaningful for Canine Cutaneous Mast Cell Tumors.
    Christof A Bertram, Alexander Bartel, Taryn A Donovan, Matti Kiupel.
      Cell division through mitosis (microscopically visible as mitotic figures, MFs) is a highly regulated process. However, neoplastic cells may exhibit errors in chromosome segregation (microscopically visible as atypical mitotic figures, AMFs) resulting in aberrant chromosome structures. AMFs have been shown to be of prognostic relevance for some neoplasms in humans but not in animals. In this study, the prognostic relevance of AMFs was evaluated for canine cutaneous mast cell tumors (ccMCT). Histological examination was conducted by one pathologist in whole slide images of 96 cases of ccMCT with a known survival time. Tumor-related death occurred in 11/18 high-grade and 2/78 low-grade cases (2011 two-tier system). The area under the curve (AUC) was 0.859 for the AMF count and 0.880 for the AMF to MF ratio with regard to tumor-related mortality. In comparison, the AUC for the mitotic count was 0.885. Based on our data, a prognostically meaningful threshold of ≥3 per 2.37 mm2 for the AMF count (sensitivity: 76.9%, specificity: 98.8%) and >7.5% for the AMF:MF ratio (sensitivity: 76.9%, specificity: 100%) is suggested. While the mitotic count of ≥ 6 resulted in six false positive cases, these could be eliminated when combined with the AMF to MF ratio. In conclusion, the results of this study suggests that AMF enumeration is a prognostically valuable test, particularly due to its high specificity with regard to tumor-related mortality. Additional validation and reproducibility studies are needed to further evaluate AMFs as a prognostic criterion for ccMCT and other tumor types.
    Keywords:  atypical mitotic figure; cell division; digital microscopy; dog; mast cell tumor; mitotic count; mitotic index; outcome; prognosis; survival time
    DOI:  https://doi.org/10.3390/vetsci11010005
  5. Biomolecules. 2023 Dec 24. pii: 28. [Epub ahead of print]14(1):
    Gross Chromosomal Rearrangement at Centromeres.
    Ran Xu, Ziyi Pan, Takuro Nakagawa.
      Centromeres play essential roles in the faithful segregation of chromosomes. CENP-A, the centromere-specific histone H3 variant, and heterochromatin characterized by di- or tri-methylation of histone H3 9th lysine (H3K9) are the hallmarks of centromere chromatin. Contrary to the epigenetic marks, DNA sequences underlying the centromere region of chromosomes are not well conserved through evolution. However, centromeres consist of repetitive sequences in many eukaryotes, including animals, plants, and a subset of fungi, including fission yeast. Advances in long-read sequencing techniques have uncovered the complete sequence of human centromeres containing more than thousands of alpha satellite repeats and other types of repetitive sequences. Not only tandem but also inverted repeats are present at a centromere. DNA recombination between centromere repeats can result in gross chromosomal rearrangement (GCR), such as translocation and isochromosome formation. CENP-A chromatin and heterochromatin suppress the centromeric GCR. The key player of homologous recombination, Rad51, safeguards centromere integrity through conservative noncrossover recombination between centromere repeats. In contrast to Rad51-dependent recombination, Rad52-mediated single-strand annealing (SSA) and microhomology-mediated end-joining (MMEJ) lead to centromeric GCR. This review summarizes recent findings on the role of centromere and recombination proteins in maintaining centromere integrity and discusses how GCR occurs at centromeres.
    Keywords:  CENP-A; DNA recombination; DNA repair; DNA repeat; centromere; fission yeast; gross chromosomal rearrangement; heterochromatin; humans; isochromosome
    DOI:  https://doi.org/10.3390/biom14010028
  6. Pharmaceutics. 2023 Dec 29. pii: 56. [Epub ahead of print]16(1):
    Maximizing Anticancer Response with MPS1 and CENPE Inhibition Alongside Apoptosis Induction.
    Bárbara Pinto, João P N Silva, Patrícia M A Silva, Daniel José Barbosa, Bruno Sarmento, Juliana Carvalho Tavares, Hassan Bousbaa.
      Antimitotic compounds, targeting key spindle assembly checkpoint (SAC) components (e.g., MPS1, Aurora kinase B, PLK1, KLP1, CENPE), are potential alternatives to microtubule-targeting antimitotic agents (e.g., paclitaxel) to circumvent resistance and side effects associated with their use. They can be classified into mitotic blockers, causing SAC-induced mitotic arrest, or mitotic drivers, pushing cells through aberrant mitosis by overriding SAC. These drugs, although advancing to clinical trials, exhibit unsatisfactory cancer treatment outcomes as monotherapy, probably due to variable cell fate responses driven by cyclin B degradation and apoptosis signal accumulation networks. We investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic navitoclax in lung cancer cells treated with the selective CENPE inhibitor GSK923295 (mitotic blocker) or the MPS1 inhibitor BAY1217389 (mitotic driver). Our aim was to steer treated cancer cells towards cell death. BH3-mimetics, in combination with both mitotic blockers and drivers, induced substantial cell death, mainly through apoptosis, in 2D and 3D cultures. Crucially, these synergistic concentrations were less toxic to non-tumor cells. This highlights the significance of combining BH3-mimetics with antimitotics, either blockers or drivers, which have reached the clinical trial phase, to enhance their effectiveness.
    Keywords:  BCL-2 family inhibitor; CENPE inhibitor; MPS1 inhibitor; antimitotics; antitumoral activity; cancer treatment; combination therapy
    DOI:  https://doi.org/10.3390/pharmaceutics16010056
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