bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024–03–24
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. A fast-acting lipid checkpoint in G1 prevents mitotic defects.
  2. A comprehensive review on role of Aurora kinase inhibitors (AKIs) in cancer therapeutics.
  3. Efficient formation of single-copy human artificial chromosomes.
  4. Mitotic bookmarking by transcription factors: be aware of redundancy.
  5. Positioning centrioles and centrosomes.
  6. Mitotic waves in frog egg extracts: Transition from phase waves to trigger waves.
  7. BUB1/KIF14 complex promotes anaplastic thyroid carcinoma progression by inducing chromosome instability.
  8. Mitochondria-ER contact sites expand during mitosis.
  9. AURKB promotes bladder cancer progression by deregulating the p53 DNA damage response pathway via MAD2L2.
  1. Nat Commun. 2024 Mar 18. 15(1): 2441
    A fast-acting lipid checkpoint in G1 prevents mitotic defects.
    Marielle S Köberlin, Yilin Fan, Chad Liu, Mingyu Chung, Antonio F M Pinto, Peter K Jackson, Alan Saghatelian, Tobias Meyer.
      Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.
    DOI:  https://doi.org/10.1038/s41467-024-46696-9
  2. Int J Biol Macromol. 2024 Mar 18. pii: S0141-8130(24)01717-3. [Epub ahead of print] 130913
    A comprehensive review on role of Aurora kinase inhibitors (AKIs) in cancer therapeutics.
    Deepali Gupta, Mukesh Kumar, Sana Saifi, Shivani Rawat, A S Ethayathulla, Punit Kaur.
      Aurora kinases (AURKs) are a family of serine /threonine protein kinases that have a crucial role in cell cycle process mainly in the event of chromosomal segregation, centrosome maturation and cytokinesis. The family consists of three members including Aurora kinase A (AURK-A), Aurora kinase B (AURK-B) and Aurora kinase C (AURK-C). All AURKs contain a conserved kinase domain for their activity but differ in their cellular localization and functions. AURK-A and AURK-B is expressed mainly in somatic cells while the expression of AURK-C is limited to germ cells. AURK-A promotes G2 to M transition of cell cycle by controlling centrosome maturation and mitotic spindle assembly. AURK-B and AURK-C form the chromosome passenger complex (CPC) that ensures proper chromosomal alignments and segregation. Aberrant expression of AURK-A and AURK-B has been detected in several solid tumours and malignancies. Hence, they have become an attractive therapeutic target against cancer. The first part of this review focuses on AURKs structure, functions, subcellular localization, and their role in tumorigenesis. The review also highlights the functional and clinical impact of selective as well as pan kinase inhibitors Currently, >60 compounds that target AURKs are in preclinical and clinical studies. The drawbacks of existing inhibitors like selectivity, drug resistance and toxicity have also been addressed. Since, majority of inhibitors are Aurora kinase inhibitor (AKI) type-1 that bind to the active (DFGin and Cin) conformation of the kinase, this information may be utilized to design highly selective kinase inhibitors that can be combined with other therapeutic agents for better clinical outcomes.
    Keywords:  Aurora kinase inhibitor (AKI); Aurora kinases (AURKs); Cancer chemotherapeutics; Cell cycle; Chromosomal passenger complex (CPC)
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.130913
  3. Science. 2024 Mar 22. 383(6689): 1344-1349
    Efficient formation of single-copy human artificial chromosomes.
    Craig W Gambogi, Gabriel J Birchak, Elie Mer, David M Brown, George Yankson, Kathryn Kixmoeller, Janardan N Gavade, Josh L Espinoza, Prakriti Kashyap, Chris L Dupont, Glennis A Logsdon, Patrick Heun, John I Glass, Ben E Black.
      Large DNA assembly methodologies underlie milestone achievements in synthetic prokaryotic and budding yeast chromosomes. While budding yeast control chromosome inheritance through ~125-base pair DNA sequence-defined centromeres, mammals and many other eukaryotes use large, epigenetic centromeres. Harnessing centromere epigenetics permits human artificial chromosome (HAC) formation but is not sufficient to avoid rampant multimerization of the initial DNA molecule upon introduction to cells. We describe an approach that efficiently forms single-copy HACs. It employs a ~750-kilobase construct that is sufficiently large to house the distinct chromatin types present at the inner and outer centromere, obviating the need to multimerize. Delivery to mammalian cells is streamlined by employing yeast spheroplast fusion. These developments permit faithful chromosome engineering in the context of metazoan cells.
    DOI:  https://doi.org/10.1126/science.adj3566
  4. Trends Biochem Sci. 2024 Mar 18. pii: S0968-0004(24)00064-1. [Epub ahead of print]
    Mitotic bookmarking by transcription factors: be aware of redundancy.
    Miguel V Silva, Diogo S Castro.
      A recent report by Chervova, Molliex, et al. shows redundant functions for the transcription factors (TFs) ESRRB and NR5A2 as mitotic bookmarkers in mouse embryonic stem (ES) cells. These occupy some of their target sites in mitotic chromatin, ensuring their robust reactivation after cell division, including markers and regulators of pluripotency.
    Keywords:  cell identity; mitotic bookmarking by transcription factors; nuclear receptors; pluripotency network; transcription
    DOI:  https://doi.org/10.1016/j.tibs.2024.03.003
  5. J Cell Biol. 2024 Apr 01. pii: e202311140. [Epub ahead of print]223(4):
    Positioning centrioles and centrosomes.
    Matthew R Hannaford, Nasser M Rusan.
      Centrosomes are the primary microtubule organizer in eukaryotic cells. In addition to shaping the intracellular microtubule network and the mitotic spindle, centrosomes are responsible for positioning cilia and flagella. To fulfill these diverse functions, centrosomes must be properly located within cells, which requires that they undergo intracellular transport. Importantly, centrosome mispositioning has been linked to ciliopathies, cancer, and infertility. The mechanisms by which centrosomes migrate are diverse and context dependent. In many cells, centrosomes move via indirect motor transport, whereby centrosomal microtubules engage anchored motor proteins that exert forces on those microtubules, resulting in centrosome movement. However, in some cases, centrosomes move via direct motor transport, whereby the centrosome or centriole functions as cargo that directly binds molecular motors which then walk on stationary microtubules. In this review, we summarize the mechanisms of centrosome motility and the consequences of centrosome mispositioning and identify key questions that remain to be addressed.
    DOI:  https://doi.org/10.1083/jcb.202311140
  6. bioRxiv. 2024 Mar 07. pii: 2024.01.18.576267. [Epub ahead of print]
    Mitotic waves in frog egg extracts: Transition from phase waves to trigger waves.
    Owen Puls, Daniel Ruiz-Reynés, Franco Tavella, Minjun Jin, Yeonghoon Kim, Lendert Gelens, Qiong Yang.
      Cyclin-dependent kinase 1 (Cdk1) activity rises and falls throughout the cell cycle, a cell-autonomous process known as mitotic oscillations. These oscillators can synchronize when spatially coupled, providing a crucial foundation for rapid synchronous divisions in large early embryos like Drosophila ( ∼ 0.5 mm) and Xenopus ( ∼ 1.2 mm). While diffusion alone cannot achieve such long-range coordination, recent studies have proposed two types of mitotic waves, phase and trigger waves, to explain the phenomena. How the waves establish over time for efficient spatial coordination remains unclear. Using Xenopus laevis egg extracts and a Cdk1 FRET sensor, we observe a transition from phase waves to a trigger wave regime in an initially homogeneous cytosol. Adding nuclei accelerates such transition. Moreover, the system transitions almost immediately to this regime when externally driven by metaphase-arrested extracts from the boundary. Employing computational modeling, we pinpoint how wave nature, including speed-period relation, depends on transient dynamics and oscillator properties, suggesting that phase waves appear transiently due to the time required for trigger waves to entrain the system and that spatial heterogeneity promotes entrainment. Therefore, we show that both waves belong to a single biological process capable of coordinating the cell cycle over long distances.
    DOI:  https://doi.org/10.1101/2024.01.18.576267
  7. J Cell Mol Med. 2024 Apr;28(7): e18182
    BUB1/KIF14 complex promotes anaplastic thyroid carcinoma progression by inducing chromosome instability.
    Tiefeng Jin, Lingling Ding, Jinming Chen, Xiaozhou Zou, Tong Xu, Zixue Xuan, Shanshan Wang, Jianqiang Chen, Wei Wang, Chaozhuang Zhu, Yiwen Zhang, Ping Huang, Zongfu Pan, Minghua Ge.
      Chromosome instability (CIN) is a common contributor driving the formation and progression of anaplastic thyroid cancer (ATC), but its mechanism remains unclear. The BUB1 mitotic checkpoint serine/threonine kinase (BUB1) is responsible for the alignment of mitotic chromosomes, which has not been thoroughly studied in ATC. Our research demonstrated that BUB1 was remarkably upregulated and closely related to worse progression-free survival. Knockdown of BUB1 attenuated cell viability, invasion, migration and induced cell cycle arrests, whereas overexpression of BUB1 promoted the cell cycle progression of papillary thyroid cancer cells. BUB1 knockdown remarkably repressed tumour growth and tumour formation of nude mice with ATC xenografts and suppressed tumour metastasis in a zebrafish xenograft model. Inhibition of BUB1 by its inhibitor BAY-1816032 also exhibited considerable anti-tumour activity. Further studies showed that enforced expression of BUB1 evoked CIN in ATC cells. BUB1 induced CIN through phosphorylation of KIF14 at serine1292 (Ser1292 ). Overexpression of the KIF14ΔSer1292 mutant was unable to facilitate the aggressiveness of ATC cells when compared with that of the wild type. Collectively, these findings demonstrate that the BUB1/KIF14 complex drives the aggressiveness of ATC by inducing CIN.
    Keywords:  BUB1 mitotic checkpoint serine/threonine kinase; anaplastic thyroid carcinoma; chromosome instability; phosphorylation; proliferation
    DOI:  https://doi.org/10.1111/jcmm.18182
  8. iScience. 2024 Apr 19. 27(4): 109379
    Mitochondria-ER contact sites expand during mitosis.
    Fang Yu, Raphael Courjaret, Lama Assaf, Asha Elmi, Ayat Hammad, Melanie Fisher, Mark Terasaki, Khaled Machaca.
      Mitochondria-ER contact sites (MERCS) are involved in energy homeostasis, redox and Ca2+ signaling, and inflammation. MERCS are heavily studied; however, little is known about their regulation during mitosis. Here, we show that MERCS expand during mitosis in three cell types using various approaches, including transmission electron microscopy, serial EM coupled to 3D reconstruction, and a split GFP MERCS marker. We further show enhanced Ca2+ transfer between the ER and mitochondria using either direct Ca2+ measurements or by quantifying the activity of Ca2+-dependent mitochondrial dehydrogenases. Collectively, our results support a lengthening of MERCS in mitosis that is associated with improved Ca2+ coupling between the two organelles. This augmented Ca2+ coupling could be important to support the increased energy needs of the cell during mitosis.
    Keywords:  Biological sciences; Cell biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.109379
  9. J Transl Med. 2024 Mar 21. 22(1): 295
    AURKB promotes bladder cancer progression by deregulating the p53 DNA damage response pathway via MAD2L2.
    Linzhi Li, Pengcheng Jiang, Weimin Hu, Fan Zou, Ming Li, Ting Rao, Yuan Ruan, Weimin Yu, Jinzhuo Ning, Fan Cheng.
       BACKGROUND: Bladder cancer (BC) is the most common urinary tract malignancy. Aurora kinase B (AURKB), a component of the chromosomal passenger protein complex, affects chromosomal segregation during cell division. Mitotic arrest-deficient 2-like protein 2 (MAD2L2) interacts with various proteins and contributes to genomic integrity. Both AURKB and MAD2L2 are overexpressed in various human cancers and have synergistic oncogenic effects; therefore, they are regarded as emerging therapeutic targets for cancer. However, the relationship between these factors and the mechanisms underlying their oncogenic activity in BC remains largely unknown. The present study aimed to explore the interactions between AURKB and MAD2L2 and how they affect BC progression via the DNA damage response (DDR) pathway.
    METHODS: Bioinformatics was used to analyze the expression, prognostic value, and pro-tumoral function of AURKB in patients with BC. CCK-8 assay, colony-forming assay, flow cytometry, SA-β-gal staining, wound healing assay, and transwell chamber experiments were performed to test the viability, cell cycle progression, senescence, and migration and invasion abilities of BC cells in vitro. A nude mouse xenograft assay was performed to test the tumorigenesis ability of BC cells in vivo. The expression and interaction of proteins and the occurrence of the senescence-associated secretory phenotype were detected using western blot analysis, co-immunoprecipitation assay, and RT-qPCR.
    RESULTS: AURKB was highly expressed and associated with prognosis in patients with BC. AURKB expression was positively correlated with MAD2L2 expression. We confirmed that AURKB interacts with, and modulates the expression of, MAD2L2 in BC cells. AURKB knockdown suppressed the proliferation, migration, and invasion abilities of, and cell cycle progression in, BC cells, inducing senescence in these cells. The effects of AURKB knockdown were rescued by MAD2L2 overexpression in vitro and in vivo. The effects of MAD2L2 knockdown were similar to those of AURKB knockdown. Furthermore, p53 ablation rescued the MAD2L2 knockdown-induced suppression of BC cell proliferation and cell cycle arrest and senescence in BC cells.
    CONCLUSIONS: AURKB activates MAD2L2 expression to downregulate the p53 DDR pathway, thereby promoting BC progression. Thus, AURKB may serve as a potential molecular marker and a novel anticancer therapeutic target for BC.
    Keywords:  Aurora kinase B; Bladder cancer; Mitotic arrest-deficient 2-like protein 2; p53
    DOI:  https://doi.org/10.1186/s12967-024-05099-6
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