bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2023–10–29
eight papers selected by
Valentina Piano, Uniklinik Köln
  1. Interplay between the plasma membrane and cell-cell adhesion maintains epithelial identity for correct polarised cell divisions.
  2. Cortical tension drug screen links mitotic spindle integrity to Rho pathway.
  3. PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability.
  4. The pathophysiology of the cell cycle in cancer and treatment strategies using various cell cycle checkpoint inhibitors.
  5. Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles.
  6. Inducing Mitotic Catastrophe as a Therapeutic Approach to Improve Outcomes in Ewing Sarcoma.
  7. Proteomic Analysis Reveals a PLK1-Dependent G2/M Degradation Program and Links PKA-AKAP2 to Cell Cycle Control.
  8. Chromatin bridges: stochastic breakage or regulated resolution?
  1. J Cell Sci. 2023 Oct 27. pii: jcs.261701. [Epub ahead of print]
    Interplay between the plasma membrane and cell-cell adhesion maintains epithelial identity for correct polarised cell divisions.
    Manal M Hosawi, Jiaoqi Cheng, Maria Fankhaenel, Marcin R Przewloka, Salah Elias.
      Polarised epithelial cell divisions represent a fundamental mechanism for tissue maintenance and morphogenesis. Morphological and mechanical changes in the plasma membrane influence the organisation and crosstalk of microtubules and actin at the cell cortex, thereby regulating the mitotic spindle machinery and chromosome segregation. Yet, the precise mechanisms linking plasma membrane remodelling to cell polarity and cortical cytoskeleton dynamics to ensure accurate execution of mitosis in mammalian epithelial cells remain poorly understood. Here we experimentally manipulated the density of mammary epithelial cells in culture, which led to several mitotic defects. Perturbation of cell-cell adhesion formation impairs the dynamics of the plasma membrane, affecting the shape and size of mitotic cells and resulting in defects in mitosis progression and generating daughter cells with aberrant architecture. In these conditions, F-actin-astral microtubule crosstalk is impaired, leading to mitotic spindle misassembly and misorientation, which in turn contributes to chromosome mis-segregation. Mechanistically, we identify the S100 Ca2+-binding protein A11 (S100A11) as a key membrane-associated regulator that forms a complex with E-cadherin and the Leucine-Glycine-Asparagine repeat protein (LGN) to coordinate plasma membrane remodelling with E-cadherin-mediated cell adhesion and LGN-dependent mitotic spindle machinery. Thus, plasma membrane-mediated maintenance of mammalian epithelial cell identity is crucial for correct execution of polarised cell divisions, genome maintenance and safeguarding tissue integrity.
    Keywords:  Cell-cell adhesion; Chromosome segregation; Epithelial identity; Mitotic spindle; Plasma membrane remodelling; Polarised cell divisions
    DOI:  https://doi.org/10.1242/jcs.261701
  2. Curr Biol. 2023 10 23. pii: S0960-9822(23)01268-X. [Epub ahead of print]33(20): 4458-4469.e4
    Cortical tension drug screen links mitotic spindle integrity to Rho pathway.
    Dejiang Wang, Yao Wang, Xiangjun Di, Fan Wang, Amanda Wanninayaka, Michael Carnell, Edna C Hardeman, Dayong Jin, Peter W Gunning.
      Mechanical force generation plays an essential role in many cellular functions, including mitosis. Actomyosin contractile forces mediate changes in cell shape in mitosis and are implicated in mitotic spindle integrity via cortical tension. An unbiased screen of 150 small molecules that impact actin organization and 32 anti-mitotic drugs identified two molecular targets, Rho kinase (ROCK) and tropomyosin 3.1/2 (Tpm3.1/2), whose inhibition has the greatest impact on mitotic cortical tension. The converse was found for compounds that depolymerize microtubules. Tpm3.1/2 forms a co-polymer with mitotic cortical actin filaments, and its inhibition prevents rescue of multipolar spindles induced by anti-microtubule chemotherapeutics. We examined the role of mitotic cortical tension in this rescue mechanism. Inhibition of ROCK and Tpm3.1/2 and knockdown (KD) of cortical nonmuscle myosin 2A (NM2A), all of which reduce cortical tension, inhibited rescue of multipolar mitotic spindles, further implicating cortical tension in the rescue mechanism. GEF-H1 released from microtubules by depolymerization increased cortical tension through the RhoA pathway, and its KD also inhibited rescue of multipolar mitotic spindles. We conclude that microtubule depolymerization by anti-cancer drugs induces cortical-tension-based rescue to ensure integrity of the mitotic bipolar spindle mediated via the RhoA pathway. Central to this mechanism is the dependence of NM2A on Tpm3.1/2 to produce the functional engagement of actin filaments responsible for cortical tension.
    Keywords:  NM2A; ROCK; Tpm3.1; actin; astral microtubules; cell cortex; cortical tension; microtubule depolymerizers; mitotic spindle; tropomyosin
    DOI:  https://doi.org/10.1016/j.cub.2023.09.022
  3. EMBO Rep. 2023 Oct 27. e57234
    PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability.
    Matteo Burigotto, Vincenza Vigorito, Colin Gliech, Alessia Mattivi, Sabrina Ghetti, Alessandra Bisio, Graziano Lolli, Andrew J Holland, Luca L Fava.
      53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic stopwatch) pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. Here, we show that Polo-like kinase 1 (PLK1) activity is essential for the time-dependent release of 53BP1 from kinetochores. PLK1 inhibition, which leads to 53BP1 persistence at kinetochores, prevents cytosolic 53BP1 association with p53 and results in a blunted MSP. Strikingly, the identification of CENP-F as the kinetochore docking partner of 53BP1 enabled us to show that measurement of mitotic timing by the MSP does not take place at kinetochores, as perturbing CENP-F-53BP1 binding had no measurable impact on the MSP. Taken together, we propose that PLK1 supports the MSP by generating a cytosolic pool of 53BP1 and that an unknown cytosolic mechanism enables the measurement of mitotic duration.
    Keywords:  53BP1; PLK1; kinetochore; mitotic stopwatch pathway; mitotic surveillance pathway
    DOI:  https://doi.org/10.15252/embr.202357234
  4. Pathol Res Pract. 2023 Oct 04. pii: S0344-0338(23)00555-1. [Epub ahead of print]251 154854
    The pathophysiology of the cell cycle in cancer and treatment strategies using various cell cycle checkpoint inhibitors.
    Sami G Almalki.
      The cell cycle is the series of events that occur in a cell leading to its division and duplication. It can be divided into two main stages: interphase and mitosis. Interphase is the longest stage of the cell cycle and can be further divided into three phases: G1, S, and G2. During G1, the cell grows and prepares for DNA synthesis. In the S phase, DNA synthesis occurs, leading to the replication of the genetic material. In G2, the cell continues to grow and prepares for mitosis. After mitosis, the cell enters the final stage of the cell cycle, called cytokinesis, during which the cytoplasm is divided, resulting in two separate daughter cells. The cell cycle then begins again with interphase. Cell cycle dysregulation is a hallmark of cancer, and it can have several consequences that contribute to the development and progression of cancer. Cyclin inhibitors and checkpoint activators have shown promise in the treatment of cancer, particularly in combination with other therapies.
    Keywords:  Cancer; Cell cycle; Checkpoint; Cyclin
    DOI:  https://doi.org/10.1016/j.prp.2023.154854
  5. PLoS Biol. 2023 Oct;21(10): e3002339
    Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles.
    Amber S Zhou, John B Tucker, Christina M Scribano, Andrew R Lynch, Caleb L Carlsen, Sophia T Pop-Vicas, Srishrika M Pattaswamy, Mark E Burkard, Beth A Weaver.
      Microtubule-targeted agents are commonly used for cancer treatment, though many patients do not benefit. Microtubule-targeted drugs were assumed to elicit anticancer activity via mitotic arrest because they cause cell death following mitotic arrest in cell culture. However, we recently demonstrated that intratumoral paclitaxel concentrations are insufficient to induce mitotic arrest and rather induce chromosomal instability (CIN) via multipolar mitotic spindles. Here, we show in metastatic breast cancer and relevant human cellular models that this mechanism is conserved among clinically useful microtubule poisons. While multipolar divisions typically produce inviable progeny, multipolar spindles can be focused into near-normal bipolar spindles at any stage of mitosis. Using a novel method to quantify the rate of CIN, we demonstrate that cell death positively correlates with net loss of DNA. Spindle focusing decreases CIN and causes resistance to diverse microtubule poisons, which can be counteracted by addition of a drug that increases CIN without affecting spindle polarity. These results demonstrate conserved mechanisms of action and resistance for diverse microtubule-targeted agents. Trial registration: clinicaltrials.gov, NCT03393741.
    DOI:  https://doi.org/10.1371/journal.pbio.3002339
  6. Cancers (Basel). 2023 Oct 10. pii: 4911. [Epub ahead of print]15(20):
    Inducing Mitotic Catastrophe as a Therapeutic Approach to Improve Outcomes in Ewing Sarcoma.
    Soumya M Turaga, Vikalp Vishwakarma, Stacey L Hembruff, Benjamin K Gibbs, Priya Sabu, Rajni V Puri, Harsh B Pathak, Glenson Samuel, Andrew K Godwin.
      Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given that phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥ 10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1-3%) and increased percentage accumulation of cells in the G2/M phase with the combination treatment (45-52%) upon cell cycle analysis, indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p ≤ 0.01), SB-743921 (p ≤ 0.01) and VIC-1911 (p ≤ 0.05). Kaplan-Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p ≤ 0.0001).
    Keywords:  Aurora kinase A; Ewing sarcoma; SB-743921; VIC-1911; drug synergy; kinesin family member 11
    DOI:  https://doi.org/10.3390/cancers15204911
  7. bioRxiv. 2023 Oct 12. pii: 2023.10.11.561963. [Epub ahead of print]
    Proteomic Analysis Reveals a PLK1-Dependent G2/M Degradation Program and Links PKA-AKAP2 to Cell Cycle Control.
    Ryan D Mouery, Carolyn Hsu, Thomas Bonacci, Derek L Bolhuis, Xianxi Wang, Christine A Mills, E Drew Toomer, Owen G Canterbury, Kevin C Robertson, Timothy B Branigan, Nicholas G Brown, Laura E Herring, Michael J Emanuele.
      Targeted protein degradation by the ubiquitin-proteasome system is an essential mechanism regulating cellular division. The kinase PLK1 coordinates protein degradation at the G2/M phase of the cell cycle by promoting the binding of substrates to the E3 ubiquitin ligase SCF βTrCP . However, the magnitude to which PLK1 shapes the mitotic proteome has not been characterized. Combining deep, quantitative proteomics with pharmacologic PLK1 inhibition (PLK1i), we identified more than 200 proteins whose abundances were increased by PLK1i at G2/M. We validate many new PLK1-regulated proteins, including several substrates of the cell cycle E3 SCF Cyclin F , demonstrating that PLK1 promotes proteolysis through at least two distinct SCF-family E3 ligases. Further, we found that the protein kinase A anchoring protein AKAP2 is cell cycle regulated and that its mitotic degradation is dependent on the PLK1/βTrCP-signaling axis. Interactome analysis revealed that the strongest interactors of AKAP2 function in signaling networks regulating proliferation, including MAPK, AKT, and Hippo. Altogether, our data demonstrate that PLK1 coordinates a widespread program of protein breakdown at G2/M. We propose that dynamic proteolytic changes mediated by PLK1 integrate proliferative signals with the core cell cycle machinery during cell division. This has potential implications in malignancies where PLK1 is aberrantly regulated.
    DOI:  https://doi.org/10.1101/2023.10.11.561963
  8. Trends Genet. 2023 Oct 25. pii: S0168-9525(23)00232-9. [Epub ahead of print]
    Chromatin bridges: stochastic breakage or regulated resolution?
    Huadong Jiang, Ying Wai Chan.
      Genetic material is organized in the form of chromosomes, which need to be segregated accurately into two daughter cells in each cell cycle. However, chromosome fusion or the presence of unresolved interchromosomal linkages lead to the formation of chromatin bridges, which can induce DNA lesions and genome instability. Persistent chromatin bridges are trapped in the cleavage furrow and are broken at or after abscission, the final step of cytokinesis. In this review, we focus on recent progress in understanding the mechanism of bridge breakage and resolution. We discuss the molecular machinery and enzymes that have been implicated in the breakage and processing of bridge DNA. In addition, we outline both the immediate outcomes and genomic consequences induced by bridge breakage.
    Keywords:  ANKLE1; TREX1; breakage–fusion–bridge cycle; chromatin bridge; chromothripsis; micronucleus
    DOI:  https://doi.org/10.1016/j.tig.2023.10.004
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:21.