bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2022‒10‒02
six papers selected by
Valentina Piano
Max Planck Institute of Molecular Physiology
  1. The genomic stability regulator PTIP is required for proper chromosome segregation in mitosis.
  2. Cell cycle expression of FLJ25439, a cytokinesis-associated protein, is mediated by D-box recognition and APC/C-Cdc20 regulated degradation.
  3. Aurora Kinases as Therapeutic Targets in Head and Neck Cancer.
  4. Glycan analysis of Lamin A/C protein at G2/M and S phases of the cell cycle.
  5. Zinc supplementation prevents mitotic accumulation in human keratinocyte cell lines upon environmentally relevant arsenic exposure.
  6. Targeting aurora kinase a (AURKA) in cancer: molecular docking and dynamic simulations of potential AURKA inhibitors.
  1. Cell Div. 2022 Sep 24. 17(1): 5
    The genomic stability regulator PTIP is required for proper chromosome segregation in mitosis.
    Fengxia Zhang, Mingxuan Wei, Haoran Chen, Liting Ji, Yan Nie, Jungseog Kang.
      BACKGROUND: The Pax transcription activation domain-interacting protein (PTIP) is a nuclear protein that is an essential component of H3K4 methylation for gene activation in vascular, kidney, B cell, and adipocyte development. Furthermore, it plays a key role in genomic stability in higher eukaryotic cells. It binds to 53BP1 and antagonizes inappropriate homologous recombination for a proper DNA damage response. Interestingly, an early study reported mitotic defects after PTIP inactivation, but it is not clear whether PTIP directly facilitates mitotic processes.RESULTS: Here, we showed that PTIP is essential for the mitotic integrity of HeLa cells. PTIP inactivation increases cell death during mitotic exit, which appears to result from direct mitotic defects. PTIP inactivation did not affect the G2M DNA damage checkpoint during interphase upon etoposide treatment. However, in mitosis, PTIP inactivation results in prolonged mitotic time, inefficient chromosome alignment, and increased cell death. Furthermore, PTIP localizes to the mitotic centrosome via BRCT domains at the C-terminus.
    CONCLUSION: This study reveals a novel function of PTIP in maintaining the genomic stability of higher eukaryotes during mitosis. Therefore, its deregulation, which occurs in various tumors, may destabilize the genome by introducing an abnormal DNA damage response, as well as erroneous chromosome segregation.
    Keywords:  Centrosome; Chromosome segregation; DNA damage; Genetic instability; Mitosis; PTIP
    DOI:  https://doi.org/10.1186/s13008-022-00081-4
  2. Biochem Biophys Res Commun. 2022 Sep 14. pii: S0006-291X(22)01296-7. [Epub ahead of print]630 151-157
    Cell cycle expression of FLJ25439, a cytokinesis-associated protein, is mediated by D-box recognition and APC/C-Cdc20 regulated degradation.
    Yen-Ming Lin, Chu-Han Wu, Pao-Hsien Chu, Pin Ouyang.
      The midbody is a transient structure forming out of the central spindle at late telophase. Both the midbody and central spindle have important functions ensuring completion of cytokinesis and defects in this process may lead to genetic diseases, including cancer. Thus, understanding the mechanisms that control cytokinesis during mitosis can reveal the key components taking part in some of the processes that promote accurate cell division. Our previous study showed that overexpression of FLJ25439 causes cytokinesis defect with midbody arrest and induces tetraploids with prolonged cell growth/cell cycle progression (Pan et al., 2015). Here, we extend our investigation with regard to the expression profile/regulation and cellular localization/function of FLJ25439 during mitosis/cytokinesis. Using a monoclonal antibody 2A4 we found that FLJ25439 expression is cell cycle-dependent and subjected to APC/C complex regulation. Furthermore, it is a novel substrate for the APC/C-Cdc20 complex and its degradation is proteasome-dependent through D-box recognition during mitotic exit. Immunofluorescence microscopy showed it is distributed at the central spindle and midbody, two structures considered important for completion of cell division, in telophase and cytokinesis, respectively, during cell cycle progression. Depletion of FLJ25439 expression revealed defects in chromosome alignment/segregation and delayed mitosis/cytokinesis progression. We thus conclude that FLJ25439 is a hitherto undiscovered factor involved in cytokinesis regulation.
    Keywords:  APC/C complex; Chromosome alignment/segregation; Cytokinesis; Destruction box; FLJ25439
    DOI:  https://doi.org/10.1016/j.bbrc.2022.09.046
  3. Cancer J. 2022 Sep-Oct 01;28(5):28(5): 387-400
    Aurora Kinases as Therapeutic Targets in Head and Neck Cancer.
    Theodore T Nguyen, Flaviane N Silva, Erica A Golemis.
      ABSTRACT: The Aurora kinases (AURKA and AURKB) have attracted attention as therapeutic targets in head and neck squamous cell carcinomas. Aurora kinases were first defined as regulators of mitosis that localization to the centrosome (AURKA) and centromere (AURKB), governing formation of the mitotic spindle, chromatin condensation, activation of the core mitotic kinase CDK1, alignment of chromosomes at metaphase, and other processes. Subsequently, additional roles for Aurora kinases have been defined in other phases of cell cycle, including regulation of ciliary disassembly and DNA replication. In cancer, elevated expression and activity of Aurora kinases result in enhanced or neomorphic locations and functions that promote aggressive disease, including promotion of MYC expression, oncogenic signaling, stem cell identity, epithelial-mesenchymal transition, and drug resistance. Numerous Aurora-targeted inhibitors have been developed and are being assessed in preclinical and clinical trials, with the goal of improving head and neck squamous cell carcinoma treatment.
    DOI:  https://doi.org/10.1097/PPO.0000000000000614
  4. Cell Biochem Biophys. 2022 Sep 30.
    Glycan analysis of Lamin A/C protein at G2/M and S phases of the cell cycle.
    Ecem Şener Uslupehlivan, Remziye Deveci, Umut Şahar, Savaş İzzetoğlu.
      During mitosis, phosphorylation and dephosphorylation of lamins triggers the nuclear envelope disassembly/assembly. However, it hasn't been known whether lamin proteins undergo any modification other than phosphorylation during the cell cycle. Glycosylation of lamin proteins is one of the less studied post-translational modification. Glycosylation and phosphorylation compete for the same positions and interplay between two modifications generate a post-translational code in the cell. Based on this, we hypothesized that glycosylation of lamin A/C protein may be important in the regulation of the structural organization of the nuclear lamina during interphase and mitosis. We analysed the glycan units of lamin A/C protein in lung carcinoma cells synchronized at G2/M and S phases via CapLC-ESI-MS/MS. Besides, the outermost glycan units were determined using lectin blotting and gold-conjugated antibody and lectin staining. TEM studies also allowed us to observe the localization of glycosylated lamin A/C protein. With this study, we determined that lamin A/C protein shows O-glycosylation at G2/M and S phases of the cell cycle. In addition to O-GlcNAcylation and O-GalNAcylation, lamin A/C is found to be contain Gal, Fuc, Man, and Sia sugars at G2/M and S phases for the first time. Having found the glycan units of the lamin A/C protein suggests that glycosylation might have a role in the nuclear organization during the cell cycle.
    Keywords:  CapLC-ESI/MS-MS; Glycan; Lamin A/C; Monosaccharide; TEM
    DOI:  https://doi.org/10.1007/s12013-022-01102-3
  5. Toxicol Appl Pharmacol. 2022 Sep 24. pii: S0041-008X(22)00400-8. [Epub ahead of print]454 116255
    Zinc supplementation prevents mitotic accumulation in human keratinocyte cell lines upon environmentally relevant arsenic exposure.
    Mayukh Banerjee, Kavitha Yaddanapudi, J Christopher States.
      Disrupted cell cycle progression underlies the molecular pathogenesis of multiple diseases. Chronic exposure to inorganic arsenic (iAs) is a global health issue leading to multi-organ cancerous and non-cancerous diseases. Exposure to supratherapeutic concentrations of iAs causes cellular accumulation in G2 or M phase of the cell cycle in multiple cell lines by inducing cyclin B1 expression. It is not clear if iAs exposure at doses corresponding to serum levels of chronically exposed populations (∼100 nM) has any effect on cell cycle distribution. In the present study we investigated if environmentally relevant iAs exposure induced cell cycle disruption and mechanisms thereof employing two human keratinocyte cell lines (HaCaT and Ker-CT), flow cytometry, immunoblots and quantitative real-time PCR (qRT-PCR). iAs exposure (100 nM; 24 h) led to mitotic accumulation of cells in both cell lines, along with the stabilization of ANAPC11 ubiquitination targets cyclin B1 and securin, without affecting their steady state mRNA levels. This result suggested that induction of cyclin B1 and securin is modulated at the level of protein degradation. Moreover, zinc supplementation successfully prevented iAs-induced mitotic accumulation and stabilization of cyclin B1 and securin without affecting their mRNA levels. Together, these data suggest that environmentally relevant iAs exposure leads to mitotic accumulation possibly by displacing zinc from the RING finger subunit of anaphase promoting complex/cyclosome (ANAPC11), the cell cycle regulating E3 ubiquitin ligase. This early cell cycle disruptive effect of environmentally relevant iAs concentration could underpin the molecular pathogenesis of multiple diseases associated with chronic iAs exposure.
    Keywords:  Arsenic; Cell Cycle; Keratinocyte; RING Finger; Zinc
    DOI:  https://doi.org/10.1016/j.taap.2022.116255
  6. Med Oncol. 2022 Sep 30. 39(12): 246
    Targeting aurora kinase a (AURKA) in cancer: molecular docking and dynamic simulations of potential AURKA inhibitors.
    Abdullah Almilaibary.
      The Aurora family of serine/threonine kinases in mammals are key regulators of mitotic progression and are commonly upregulated in human tumors. Since AURKA's increased expression has been linked to cancer, AURKA inhibitors could reduce AURKA expression and function as potent therapeutic drugs. The study's objective was to find and categorize inhibitors with a stronger affinity for AURKA. This study also aimed to identify AURKA's expression profile and prognostic significance across pan-cancers. We looked into therapeutic compounds that were structurally comparable to MK8745 for their potential to selectively inhibit AURKA. We used drug likeliness analysis, MD simulation studies to evaluate the therapeutic possibility of screened MK8745 analogues. AURKA was found to be strongly upregulated in several cancers and is linked to worse overall and relapse-free survival. The Molecular docking and dynamic analysis revealed two new MK8745 analogues to be potent AURKA inhibitors with higher binding affinities and stabilities than MK8745. Furthermore, MK8745 analogues are potential replacements for MK8745 because they have strong binding affinity, which is consistent with MDS results, and have appropriate ADMET properties. Through basic, clinical, and preclinical research, the identification of novel compounds may open the door for their prospective use in the prevention of cancer.
    Keywords:  AURKA; Cancer; Docking; MK8745; Molecular dynamic simulation; Pan-cancer; Prognosis
    DOI:  https://doi.org/10.1007/s12032-022-01852-3
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