bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024–04–14
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. Simvastatin activates the spindle assembly checkpoint and causes abnormal cell division by modifying small GTPases.
  2. Functions of HP1 in preventing chromosomal instability.
  3. Antiparallel microtubule bundling supports KIF15-driven mitotic spindle assembly.
  4. The bistable mitotic switch in fission yeast.
  5. Mitotic gene regulation by the N-MYC-WDR5-PDPK1 nexus.
  6. Phosphorylation of ELYS promotes its interaction with VAPB at decondensing chromosomes during mitosis.
  7. Mitotic spindle positioning protein (MISP) preferentially binds to aged F-actin.
  8. The role of Aurora kinase A in hepatocellular carcinoma: Unveiling the intriguing functions of a key but still underexplored factor in liver cancer.
  9. Exploring the anticancer potential of fluoro flavone analogues: insights from molecular docking and dynamics studies with Aurora Kinase B.
  1. Cell Signal. 2024 Apr 09. pii: S0898-6568(24)00140-2. [Epub ahead of print] 111172
    Simvastatin activates the spindle assembly checkpoint and causes abnormal cell division by modifying small GTPases.
    Junna Tanaka, Hiroki Kuwajima, Ryuzaburo Yuki, Yuji Nakayama.
      Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of the cholesterol synthesis pathway. It has been used clinically as a lipid-lowering agent to reduce low-density lipoprotein (LDL) cholesterol levels. In addition, antitumor activity has been demonstrated. Although simvastatin attenuates the prenylation of small GTPases, its effects on cell division in which small GTPases play an important role, have not been examined as a mechanism underlying its cytostatic effects. In this study, we determined its effect on cell division. Cell cycle synchronization experiments revealed a delay in mitotic progression in simvastatin-treated cells at concentrations lower than the IC50. Time-lapse imaging analysis indicated that the duration of mitosis, especially from mitotic entry to anaphase onset, was prolonged. In addition, simvastatin increased the number of cells exhibiting misoriented anaphase/telophase and bleb formation. Inhibition of the spindle assembly checkpoint (SAC) kinase Mps1 canceled the mitotic delay. Additionally, the number of cells exhibiting kinetochore localization of BubR1, an essential component of SAC, was increased, suggesting an involvement of SAC in the mitotic delay. Enhancement of F-actin formation and cell rounding at mitotic entry indicates that cortical actin dynamics were affected by simvastatin. The cholesterol removal agent methyl-β-cyclodextrin (MβCD) accelerated mitotic progression differently from simvastatin, suggesting that cholesterol loss from the plasma membrane is not involved in the mitotic delay. Of note, the small GTPase RhoA, which is a critical factor for cortical actin dynamics, exhibited upregulated expression. In addition, Rap1 was likely not geranylgeranylated. Our results demonstrate that simvastatin affects actin dynamics by modifying small GTPases, thereby activating the spindle assembly checkpoint and causing abnormal cell division.
    Keywords:  Cell division; MβCD; RO-3306; Rap1; RhoA; STLC; Simvastatin
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111172
  2. Cell Biochem Funct. 2024 Apr;42(3): e4017
    Functions of HP1 in preventing chromosomal instability.
    Zexian Ding, Lei Peng, Jinghua Zeng, Kejia Yuan, Yan Tang, Qi Yi.
      Chromosomal instability (CIN), caused by errors in the segregation of chromosomes during mitosis, is a hallmark of many types of cancer. The fidelity of chromosome segregation is governed by a sophisticated cellular signaling network, one crucial orchestrator of which is Heterochromatin protein 1 (HP1). HP1 dynamically localizes to distinct sites at various stages of mitosis, where it regulates key mitotic events ranging from chromosome-microtubule attachment to sister chromatid cohesion to cytokinesis. Our evolving comprehension of HP1's multifaceted role has positioned it as a central protein in the orchestration of mitotic processes.
    Keywords:  centromere; chromosomal instability; chromosomal passenger complex; heterochromatin protein 1; kinetochore; mitosis; sister chromatid cohesion
    DOI:  https://doi.org/10.1002/cbf.4017
  3. Mol Biol Cell. 2024 Apr 10. mbcE24010023
    Antiparallel microtubule bundling supports KIF15-driven mitotic spindle assembly.
    Brittany M Salazar, Ryoma Ohi.
      The spindle is a bipolar microtubule-based machine that is crucial for accurate chromosome segregation. Spindle bipolarity is generated by Eg5 (a kinesin-5), a conserved motor that drives spindle assembly by localizing to and sliding apart antiparallel microtubules. In the presence of Eg5 inhibitors (K5Is), KIF15 (a kinesin-12) can promote spindle assembly, resulting in K5I-resistant cells (KIRCs). However, KIF15 is a less potent motor than Eg5, suggesting that other factors may contribute to spindle formation in KIRCs. Protein Regulator of Cytokinesis 1 (PRC1) preferentially bundles antiparallel microtubules, and we previously showed that PRC1 promotes KIF15-microtubule binding, leading us to hypothesize that PRC1 may enhance KIF15 activity in KIRCs. Here, we demonstrate that 1) loss of PRC1 in KIRCs decreases spindle bipolarity, 2) overexpression of PRC1 increases spindle formation efficiency in KIRCs, 3) overexpression of PRC1 protects K5I naïve cells against the Eg5 inhibitor STLC, and 4) PRC1 overexpression promotes the establishment of K5I resistance. These effects are not fully reproduced by a TPX2, a microtubule bundler with no known preference for microtubule orientation. These results suggest a model wherein PRC1-mediated bundling of microtubules creates a more favorable microtubule architecture for KIF15-driven mitotic spindle assembly in the context of Eg5 inhibition. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E24-01-0023
  4. Mol Biol Cell. 2024 Apr 10. mbcE24030142
    The bistable mitotic switch in fission yeast.
    Béla Novák, John J Tyson.
      In favorable conditions, eukaryotic cells proceed irreversibly through the cell division cycle (G1-S-G2-M) in order to produce two daughter cells with the same number and identity of chromosomes of their progenitor. The integrity of this process is maintained by 'checkpoints' that hold a cell at particular transition points of the cycle until all requisite events are completed. The crucial functions of these checkpoints seem to depend on irreversible bistability of the underlying checkpoint control systems. Bistability of cell cycle transitions has been confirmed experimentally in frog egg extracts, budding yeast cells and mammalian cells. For fission yeast cells, a recent paper by Patterson et al. (2021) provides experimental evidence for an abrupt transition from G2 phase into mitosis, and we show that these data are consistent with a stochastic model of a bistable switch governing the G2/M checkpoint. Interestingly, our model suggests that their experimental data could also be explained by a reversible/sigmoidal switch, and stochastic simulations confirm this supposition. We propose a simple modification of their experimental protocol that could provide convincing evidence for (or against) bistability of the G2/M transition in fission yeast.
    DOI:  https://doi.org/10.1091/mbc.E24-03-0142
  5. BMC Genomics. 2024 Apr 11. 25(1): 360
    Mitotic gene regulation by the N-MYC-WDR5-PDPK1 nexus.
    Sarah A Streeter, Alexandria G Williams, James R Evans, Jing Wang, Alissa D Guarnaccia, Andrea C Florian, Rafet Al-Tobasei, Qi Liu, William P Tansey, April M Weissmiller.
       BACKGROUND: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5-a critical MYC cofactor-regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein.
    RESULTS: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus.
    CONCLUSIONS: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.
    Keywords:  Chromosome segregation; Genomic instability; Mitosis; N-MYC; Neuroblastoma; PDPK1; Spindle pole; WDR5
    DOI:  https://doi.org/10.1186/s12864-024-10282-6
  6. EMBO Rep. 2024 Apr 11.
    Phosphorylation of ELYS promotes its interaction with VAPB at decondensing chromosomes during mitosis.
    Christina James, Ulrike Möller, Christiane Spillner, Sabine König, Olexandr Dybkov, Henning Urlaub, Christof Lenz, Ralph H Kehlenbach.
      ELYS is a nucleoporin that localizes to the nuclear side of the nuclear pore complex (NPC) in interphase cells. In mitosis, it serves as an assembly platform that interacts with chromatin and then with nucleoporin subcomplexes to initiate post-mitotic NPC assembly. Here we identify ELYS as a major binding partner of the membrane protein VAPB during mitosis. In mitosis, ELYS becomes phosphorylated at many sites, including a predicted FFAT (two phenylalanines in an acidic tract) motif, which mediates interaction with the MSP (major sperm protein)-domain of VAPB. Binding assays using recombinant proteins or cell lysates and co-immunoprecipitation experiments show that VAPB binds the FFAT motif of ELYS in a phosphorylation-dependent manner. In anaphase, the two proteins co-localize to the non-core region of the newly forming nuclear envelope. Depletion of VAPB results in prolonged mitosis, slow progression from meta- to anaphase and in chromosome segregation defects. Together, our results suggest a role of VAPB in mitosis upon recruitment to or release from ELYS at the non-core region of the chromatin in a phosphorylation-dependent manner.
    Keywords:  ELYS; FFAT-motif; Mitosis; Nuclear Envelope; VAPB
    DOI:  https://doi.org/10.1038/s44319-024-00125-6
  7. J Biol Chem. 2024 Apr 06. pii: S0021-9258(24)01780-0. [Epub ahead of print] 107279
    Mitotic spindle positioning protein (MISP) preferentially binds to aged F-actin.
    E Angelo Morales, Gillian N Fitz, Matthew J Tyska.
      Actin bundling proteins crosslink filaments into polarized structures that shape and support membrane protrusions including filopodia, microvilli, and stereocilia. In the case of epithelial microvilli, mitotic spindle positioning protein (MISP) is an actin bundler that localizes specifically to the basal rootlets, where the pointed ends of core bundle filaments converge. Previous studies established that MISP is prevented from binding more distal segments of the core bundle by competition with other actin binding proteins. Yet whether MISP holds a preference for binding directly to rootlet actin remains an open question. By immunostaining native intestinal tissue sections, we found that microvillar rootlets are decorated with the severing protein, cofilin, suggesting high levels of ADP-actin in these structures. Using TIRF microscopy assays, we also found that purified MISP exhibits a binding preference for ADP- vs. ADP-Pi-actin containing filaments. Consistent with this, assays with actively growing actin filaments revealed that MISP binds at or near their pointed ends. Moreover, although substrate attached MISP assembles filament bundles in parallel and antiparallel configurations, in solution MISP assembles parallel bundles consisting of multiple filaments exhibiting uniform polarity. These discoveries highlight nucleotide state sensing as a mechanism for sorting actin bundlers along filaments and driving their accumulation near filament ends. Such localized binding might drive parallel bundle formation and/or locally modulate bundle mechanical properties in microvilli and related protrusions.
    Keywords:  brush border; bundle; cytoskeleton; enterocyte; membrane; microvilli; protrusion; terminal web
    DOI:  https://doi.org/10.1016/j.jbc.2024.107279
  8. Cell Prolif. 2024 Apr 08. e13641
    The role of Aurora kinase A in hepatocellular carcinoma: Unveiling the intriguing functions of a key but still underexplored factor in liver cancer.
    Luca Grisetti, Clarissa J C Garcia, Anna A Saponaro, Claudio Tiribelli, Devis Pascut.
      Aurora Kinase A (AURKA) plays a central role as a serine/threonine kinase in regulating cell cycle progression and mitotic functions. Over the years, extensive research has revealed the multifaceted roles of AURKA in cancer development and progression. AURKA's dysregulation is frequently observed in various human cancers, including hepatocellular carcinoma (HCC). Its overexpression in HCC has been associated with aggressive phenotypes and poor clinical outcomes. This review comprehensively explores the molecular mechanisms underlying AURKA expression in HCC and its functional implications in cell migration, invasion, epithelial-to-mesenchymal transition, metastasis, stemness, and drug resistance. This work focuses on the clinical significance of AURKA as a diagnostic and prognostic biomarker for HCC. High levels of AURKA expression have been correlated with shorter overall and disease-free survival in various cohorts, highlighting its potential utility as a sensitive prognostic indicator. Recent insights into AURKA's role in modulating the tumour microenvironment, particularly immune cell recruitment, may provide valuable information for personalized treatment strategies. AURKA's critical involvement in modulating cellular pathways and its overexpression in cancer makes it an attractive target for anticancer therapies. This review discusses the evidence about novel and selective AURKA inhibitors for more effective treatments for HCC.
    DOI:  https://doi.org/10.1111/cpr.13641
  9. In Silico Pharmacol. 2024 ;12(1): 26
    Exploring the anticancer potential of fluoro flavone analogues: insights from molecular docking and dynamics studies with Aurora Kinase B.
    Ipsa A Singh, Kiran Bharat Lokhande, K Venkateswara Swamy.
      Aurora Kinase B belongs to the serine kinase family. It plays an essential role in cell division and participates in mitosis and chromatid segregation. Overexpression, polymorphism, and splicing variants in the protein lead to tumorigenesis, leading to cancer. Flavones belong to the class of flavonoids and are derived from plants and show anti-cancer activities. Fluoro flavones and their analogs are taken from the PubChem database, resulting in 3882 compounds which is 90% similar to the fluoro flavones. Lipinski's rule of five, REOS and PAINS drug-like filters were applied which resulted 2448 compounds. These compounds are docked with Aurora Kinase B using SP and XP modules of Glide software. The best binding scores for SP docking were - 9.153 kcal/mol for the compound with CID: 44298667, and XP docking was - 10.287 kcal/mol with CID: 101664315. Enrichment calculations were done using Aurora Kinase B's decoys to validate the docking result. The resulting R2 = 0.96 from enrichment calculations suggests that the docking protocol is valid. The SP and XP docking lead compounds and the Fluoro flavone were subjected to 100 ns MD simulation to probe the protein-ligand complex stability. Also, the binding free energies between the Aurora kinase B and lead compounds were computed by Prime MM/GBSA module. The result suggests that the lead compounds bind more strongly with Aurora Kinase B than the Fluoro flavone. These lead compounds can be further evaluated in vitro and in vivo and can be used as future novel drugs for the curation of cancer.
    Graphical abstract:
    Keywords:  Aurora kinase B; Cancer; Fluoro flavones; MD simulation; Molecular docking
    DOI:  https://doi.org/10.1007/s40203-024-00200-9
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